Inflammation and tumor progression: signaling pathways and targeted intervention

Despite the employment in the clinical setting of a series of strategies for cancer treatment (e.g., surgery, chemotherapy, irradiation, and immunotherapy), cancer-related mortality remains one of the leading causes of death worldwide, accounting for 13% of all human deaths. 1 Because cancer is considered a cell-intrinsic genetic disease, most treatment modalities are focused on killing tumor cells directly, with multidrug resistance of cancer cells being a crucial reason for the low efficacy of cancer therapy. 2 , 3 Inflammation has been demonstrated closely associated with all stages of development and malignant progression of most types of cancer, as well as with the efficacy of anti-cancer therapies. 4 – 6 In detail, chronic inflammation is involved in immunosuppression, thereby providing a preferred microenvironment for tumorigenesis, development, and metastasis. 7 Besides, inflammatory responses can be induced by anti-cancer therapies. 8 , 9 Acute inflammation contributes to cancer cell death by inducing an anti-tumor immune response, while therapy-elicited chronic inflammation promotes therapeutic resistance and cancer progression. The correlation between inflammation and cancer was firstly suggested by Rudolf Virchow in the mid-19th century, based on observations that cancer originated in sites of chronic inflammation, and that inflammatory cells were abundant in tumor biopsies. 10 Nowadays, cancer-related inflammation is considered as a key characteristic of cancer, with a well-established link between chronic inflammation and tumor development. 11 In fact, chronic, dysregulated, persistent, and unresolved inflammation has been associated with an increased risk of malignancies, as well as the malignant progression of cancer in most types of cancer. 4 , 5 , 12 Moreover, growing evidence have implied that the inflammatory tumor microenvironment (TME) is a key determinant for the therapeutic efficacy of conventional chemotherapy (e.g., radiotherapy and chemotherapy) and immunotherapy. 2 , 6 However, acute inflammation induced by exogenous stimulators has been reported to enhance anti-tumor immunity by promoting the maturation and function of dendritic cells (DCs) and the initiation of effector T cells. 13 Inflammation involving the innate and adaptive immune systems is known to be the protective immune response for maintaining tissue homeostasis by eliminating harmful stimuli, including damaged cells, irritants, pathogens, and sterile lesions. 5 , 14 Unlike wound healing and infection, the inflammatory response during cancer development has been demonstrated to be non-resolving. 14 Furthermore, tumor-extrinsic inflammation is known to be triggered by various factors, including autoimmune diseases, bacterial and viral infections, obesity, smoking, asbestos exposure, and excessive alcohol consumption, all of which have been reported to increase cancer risk and accelerate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation might be caused by cancer-initiating mutations and contribute to tumor progression via the recruitment and activation of inflammatory cells. 15 – 17 Both extrinsic and intrinsic inflammation are known to result in immunosuppressive TME, thereby providing a preferred condition for tumor development. Once the inflammatory TME is established, inflammatory factors derived from tumor cells or interstitial cells would induce cell proliferation and prolong cell survival by initially activating oncogenes and subsequently inactivating tumor suppressor genes. 15 , 16 Owing to the relationship between inflammation and tumor, 13 harnessing inflammation appears to be an important approach for a more efficient anti-cancer treatment. The powerful chemopreventive effects of non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, have been demonstrated in numerous clinical studies. 18 – 20 Administration of statins has also been reported to significantly reduce the risk of development of multiple types of cancer, including breast cancer, colorectal cancer (CRC), and hepatocellular carcinoma (HCC), by exerting anti-inflammatory effects. 21 – 23 In addition, increasing the level of specialized proresolving lipid mediators (SPM, e.g., lipoxin A 4 (LXA 4 ) and resolvin D1 (RVD1)) and their synthetic pathways was also shown to significantly inhibit the tumor growth. 24 – 26 Moreover, enhancing tumor immunity by blocking inhibitory checkpoints or using chimeric antigen receptor T-cell (CAR-T) immunotherapy has shown promising efficacy in certain cancer types. 27 , 28 However, side-effects of these therapies, such as coagulopathy and “cytokine storm” have hindered their full application to cancer therapy, 29 , 30 suggesting that reduction of these harmful immunotherapy-generated inflammation events would be beneficial for the outcome of patients with cancer. In brief, tumor-related chronic inflammation has been shown to promote immunosuppression of the TME and th

Vascular endothelial cells Vascular endothelial cells are known to play an important role in the inflammatory process. They are widely distributed in the inner side of the vascular cavity, forming a relatively stable barrier, separating the blood from the subcutaneous tissue. In the early stage of inflammation, they have been shown to regulate the permeability of blood vessels and affect the infiltration of inflammatory cells. 62 During inflammation, leukocyte-synthesized and released TNF-α and IL-1 cytokines have been found to promote the pro-inflammatory phenotype of endothelial cells and fibroblasts through the activation of the TNFR/IL-1 pathway and NF-κB signaling. 63 , 64 Activated endothelial cells express adhesion molecules, such as selectins and intercellular adhesion molecule (ICAM)−1, and secrete a large amount of chemokines. 65 In addition, immobilization of CXC and CC chemokines on endothelial and matrix glycosaminoglycans was reported to create a chemotactic gradient, leading to the recruitment and extravasation of neutrophils and monocytes. 66 More specifically, CXC chemokines, including CXCL8 (IL-8), macrophage inflammatory protein 2 (MIP-2, known also as CXCL2), complement C5a, leucine, and platelet-activating factor (PAF) have been reported to mediate the process of neutrophil infiltration. 66 , 67

The recruitment of monocytes and their differentiation into macrophages are essential for the onset, progression, and resolution of inflammation. During the onset of the inflammation process, the chemokine monocyte chemotactic protein (MCP)1/CCL2 was found to mediate the recruitment of pro-inflammatory monocytes expressing the chemokine receptor CCR2. 77 As the inflammation progresses, the macrophage colony-stimulating factor (M-CSF), which can promote the differentiation of monocytes to macrophages, was significantly upregulated in the inflammation site. 78 , 79 Macrophages have multiple functions and a plastic phenotype in responding to their inflammatory environment: M1 macrophages have a pro-inflammatory phenotype and produce pro-inflammatory factors, whereas M2 macrophages have immunosuppressive effects. 80 These immunosuppressive macrophages express elevated 15-lipoxygenase (15-LOX) and transforming growth factor (TGF)-β, thus dampening leukocyte trafficking, promoting efferocytosis and wound repair. 81 In addition, SPM were reported to upregulate microRNAs targeting inflammatory genes in macrophages, thereby downregulating the translation of inflammatory cytokines and chemokines. 82

T cells play a crucial role in antiviral responses through the production of cytokines. 88 T cells are activated during inflammation, and differentiate into various T-cell subsets, including T-helper (Th)1, Th2, Th17, and regulatory T (Treg) cells, depending on the cytokines secreted around the inflammation loci. In particular, Th1 cells are derived following stimulation with interferon (IFN)-γ and TNF-α and secrete IFN-γ, TNF-α, and IL-2, whereas Th2 cells are derived in the presence of IL-4 or IL-10 and secrete IL-4, IL-5, IL-9, and IL-13. In addition, Th17 cells, which secrete IL-17, IL-23, and IL-22, are derived in the presence of TGF-β, IL-1β, and IL-6. In contrast, Treg cells are raised in the presence of TGF-β, and secrete immunosuppressive cytokines, including IL-10 and TGF-β. IL-17 is known to stimulate the production of inflammatory mediators, including TNF-α, IL-6, and IL-1β, whereas Treg cells have been shown to effectively regulate the resolution of inflammation. In addition, CD4 + T cells have been reported to promote the production of virus-specific antibodies by activating B cells, whereas CD8 + T cells produce IFN-γ and TNF-α and can kill viral-infected cells. 89 T-helper cells are known to produce a variety of pro-inflammatory cytokines and chemokines by activating NF-κB signaling, recruiting lymphocytes and leukocytes to the site of inflammation, where all these immune cells express and secrete additional chemokines and cytokines amplifying the inflammatory process in response to viral infections. 90

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells involved in the regulation of acute and chronic inflammatory conditions such as autoimmune and infectious diseases. 96 It is known that MDSCs can be recruited into inflamed tissues where they trigger the resolution of inflammation. 96 Various studies show MDSCs suppress the activity of immune cells through different mechanisms involving the degradation of L-arginine, the production of ROS, and the secretion of anti-inflammatory cytokines like IL-10 and TGF-β. 97 In addition, MDSCs can inhibit T cell activity by downregulating the pro-inflammatory cytokines, such as IL-12 and prostaglandin E 2 (PGE 2 ). 98

Natural killer (NK) and B cells are also involved in the inflammatory process. For instance, NK cells are important immunosurveillance cells that detect infected, transformed, or stressed cells with their activating receptors NKG2D and NKp46. 104 Once activated, NK cells become cytotoxic and release lytic granules (perforin, granzymes) or induce death signals (e.g. TNF-related apoptosis-inducing ligand (TRAIL)/TRAL-R, Fas ligand (Fas-L)/Fas), thereby kill microorganisms. 105 B cells are transformed into plasma cells and secrete antibodies to kill microorganisms, in a mechanism called antibody-dependent cell-mediated cytotoxicity (ADCC). Macrophages, B cells, and DCs are also known to activate T cells through antigen cross-presentation. 106 , 107 However, the chemotactic mechanisms driving the recruitment of monocytes to repair tissues as the inflammation progresses, are not well understood. 106 Still, the phenotype of monocytes at the site of inflammation has been demonstrated to be dynamically regulated by inflammatory cytokines and mediators. These pro- and anti-inflammatory factors were reported to lead to the production of subpopulations of macrophages with different functional characteristics that regulated the activity of fibroblast cells, matrix metabolism, angiogenesis, and promoted tissue repair processes. 78 , 79

In order to prevent the progression from acute-resolving to persistent-chronic inflammation and allow organs to restore homeostasis, the inflammatory reaction must be actively resolved, to prevent further tissue damage. 170 , 171 Historically, it was believed that the resolution of inflammation was a passive process involving the dilution of chemokine gradients over time, thus stopping the recruitment of circulating leukocytes to the site of injury. 172 However, extensive work over the past few decades has revealed that the resolution of inflammation is a programmed active process, and deficiency in any of its components might lead to overactive, uncontrolled chronic inflammation. With the advancement of lipidomics and metabolomics, Serhan et al. showed that the resolution phase of inflammation is regulated by a class of enzymatically produced SPM. 36 , 173 They also introduced the quantitative resolution indices (defined as follows: T max : time point when PMN infiltration to maximum; Ѱ max : PMN maximum number; T 50 : time point when PMNs reduction to half of Ѱ max ; Ѱ 50 : 50% of Ѱ max ; R i : resolution interval, time interval from T max to T 50 ; K 50 : the rate of PMN reduction from T max to T 50 ), which indicated reduced PMN infiltration and shortened resolution interval after SPM biosynthesized. 174 Upon inflammation initiation, the pro-inflammatory lipid mediators (LM) are produced, whereas during the resolution of inflammation, the SPM are abundantly biosynthesized, i.e., LM class switching occurs (Fig. 1 ). SPM have been shown to not only function as signals for the termination of the inflammatory response, but also promote macrophages to engulf dead cells to accelerate the resolution of inflammation. Removal of apoptotic neutrophils by macrophages is a prerequisite for macrophage efferocytosis, which has been reported to coincide with the biosynthesis of SPM, reducing the expression of pro-inflammatory lipid mediators and cytokines. Fig. 1 SPM biosynthesis and their roles in the resolution of inflammation. a SPM including lipoxins, E-series resolvins, D-series resolvins, protectins (neuroprotectin D1), and maresins are biosynthesized from arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The main structures of these SPM and their receptors are depicted. b Anti-inflammatory lipid mediators (LM) class are produced to help restore tissue homeostasis during the resolution of inflammation Lipoxins are a class of metabolite derivatives of AA via the lipoxygenase pathway. In the vascular cavity, leukocyte-derived 5-LOX is known to catalyzes the synthesis of leukotriene A4 (LTA 4 ) which is then catalyzed by platelet-derived 12-LOX to produce LXA 4 or LXB 4 . 175 Lipoxins have also been found to be catalyzed by 15-LOX in epithelial cells, monocytes, and eosinophils to produce intermediate products, followed by their catalysis by 5-LOX in neutrophils to produce LXA 4 or LXB 4 . Serhan et al. discovered that aspirin-mediated acetylation of COX2 inhibited the production of prostaglandin but led to the conversion of AA to 15(R)-hydroxyeicosatetraenoic acid (15(R)-HETE), a substrate used for the synthesis of 15-epi-lipoxins (AT-lipoxins). In addition, lipoxins have been reported to promote the resolution of inflammation through activating lipoxin receptor (ALX)/N-formyl peptide receptor (FPR)−2 receptors to antagonize pro-inflammatory mediators, resulting in decreased recruitment of leukocytes and deactivation of NF-κB, decreased production of superoxide, and diminished production of pro-inflammatory chemokines/cytokines. 176 , 177 Resolvins are another series of important endogenous SPM. Depending on their source, they either contain E-series (RvE) derived from eicosapentaenoic acid (EPA), D-series (RvD) from docosahexaenoic acid (DHA) and aspirin-triggered resolvin D (AT-RvD1-RvD6), or Dp series (RvD n-3DPA ) derived from docosapentaenoic acid (DPA). 178 – 180 Resolvins are synthesized through interactions between the activities of aspirin-acetylated COX2 and LOX in endothelial cells and leukocytes. In particular, RvE1 is known to activate downstream pathways by binding to ERV1/ChemR23, leading to the inhibition of the NF-κB pathway in inflammatory cells. 181 Meanwhile, RvD1 and RvD3 exert their bioactions through binding to ALX/FPR2 and DRV1/GPR32, respectively, whereas RvD2 and RvD5 activate their DRV2/GPR18 and DRV1/GPR32 receptors, respectively. 178 , 182 , 183 Of interest, the activation of the RvE1-ERV1/ChemR23 axis has been shown to promote the apoptosis and macrophage-mediated phagocytosis of neutrophils, while reducing the production of pro-inflammatory cytokines. 184 – 186 Recently, we also found that RvD P 5 inhibited the infiltration of neutrophils and promoted the phagocytic function of macrophages through the ALX/FPR2 receptor. 187 In addition to lipoxins and resolvins, additional families of SPM, namely protectins and maresins have also been identified. Pro

As mentioned above, inflammation has been demonstrated to not only promote the immune response but also lead to immune surveillance. The innate and adaptive immunity involved in the inflammatory response were also shown to play an important role in cancer initiation, progression, and metastasis. 5 The acute inflammatory response is the first line of defense against external infection or injury, promoting innate and adaptive immune responses. The innate immune system consists of evolutionary diversified hematopoietic cells, such as neutrophils, macrophages, DCs, mast cells, and so on. 249 These cell populations are known to participate in the phagocytosis of pathogens, microorganisms, and necrotic substances, thereby mediating the resolution of inflammation. Moreover, as antigen-presenting cells, DCs and macrophages have also been shown to provide specific antigens to T cells for recognition and activation of the adaptive immune response. 250 Therefore, acute inflammation could eliminate pathogens and protect the body from infections. However, if the acute inflammatory reaction does not resolve in time, it could be transformed into chronic inflammation resulting in an immunosuppressive microenvironment with a large number of immunosuppressive cells (M2 macrophages, MDSCs, Treg cells, etc.) and cytokines. 5 , 15 These changes have been reported to promote the activation of oncogenes, DNA and protein damage, release of ROS, and affect multiple signaling pathways including NF-κB, K-RAS, and P53, leading to chronic diseases including cancer. 5 In addition, epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and noncoding RNA, play an important role in the transformation of inflammation into cancer as well as in the occurrence, development, invasion, metastasis, and drug resistance of cancer. 247 , 251 – 254 Particularly worth mentioning is the histone lactylation in macrophages that might promote inflammatory resolution and tumor immune escape, 251 , 255 – 258 but whether lactylation could modify other proteins and their effects on protein functions remain unknown. Moreover, lactic acids in the inflammatory microenvironment are known to play an important role in promoting the progression of inflammation and cancer via acting on immune cells (such as cytotoxic T cells (CTLs), DCs, and APCs), 259 – 261 and immunosuppressive cells (such as M2-macrophages, MDSCs, and Treg cells). 262 – 264 Meanwhile, gene mutations would lead to abnormal cellular proliferation, but immune cells could recognize specific antigens on these tumor cells, and stimulate immune response to clear them. Multiple inflammatory factors and signaling pathways, such as 5-LOX, COX-2, TGF-β, and VEGF are well-known molecules linking inflammation and chronic diseases. 252 What’s more, the dysregulation of inflammatory molecules or factors is often caused by aberrant inflammatory pathways that including NF-κB, MAPK, JAK-STAT, and PI3K/AKT, etc (Fig. 2 ). For instance, more than 500 cancer-related genes are regulated by the NF-κB signaling pathway. 247 Fig. 2 Inflammatory signaling pathways involved in cancer development. Intracellular signaling pathways involved in inflammation and tumor development are activated via distinct receptors at the cell membrane. Subsequent downstream signaling events activate several well-characterized pathways: NF-κB, MAPK, JAK-STAT, and PI3K-AKT. These pathways regulate various inflammatory factors The immune system is known to broadly participate in cancer-related inflammation that could precede the development of malignancy or be induced by oncogenic changes, thus generating a pro-tumor inflammatory environment. 9 In this section we retrospectively present the relationship of the innate and adaptive immune system during response to inflammation with tumor initiation and progression and discuss the outstanding questions that remain to be answered (Fig. 3 ). Fig. 3 The relationship between inflammation and cancer development. During acute inflammatory responses (left panel): after tumor antigen uptake or activation by TLR agonist, mature DCs can regulate anti-tumor immune responses by inducing inflammatory responses via multiple mechanisms, such as cross-presenting the tumor antigens and priming tumor-specific CD8 + T cells, polarizing immune cells toward tumor suppression (e.g., M1 polarization of TAMs), recruiting NK cells which can sustain T-cell responses. However, if the acute inflammatory reaction does not resolve in time, it subsequently transforms into chronic inflammation (right panel). In this microenvironment, cancer cells can not only hijack DCs to prevent TAA presentation, but also recruit a large number of immunosuppressive cells (e.g., MDSCs, Treg cells, Breg cells, M2-TAMs, N2-TANs, and Th2 cells) by secreting various cytokines, chemokines, and inflammatory mediators. In turn, these immunosuppressive cells provide a rich proangiogenic and pro-tumoral microenvironme

The adaptive immune response which occurs after the innate immune response, is a specific response of lymphocytes to antigen stimulation, followed by the immune memory effect. 351 When antigen-presenting cells (APCs) present antigens to T cells, the T-cell receptor (TCR) recognizes the antigen and activates the secretion of tumor-killer molecules, such as IFN-γ and granzymes with the action of synergistic stimulatory molecules. Meanwhile, helper T cells secrete cytokines to activate B cells, which produce antibodies, mediating the ADCC. 249 , 352 Generally, adaptive immune responses are known to inhibit tumorigenesis and progression. However, some types of T cells have been shown to mainly participate in adaptive immune responses, promoting tumor progression. In fact, Th2, Th17, and Treg cells have often been associated with tumor progression and unfavorable prognosis. 249 T-helper 2 (Th2) cells are known to not only regulate protective type 2 immune responses to extracellular pathogens, such as helminthes, but also contribute to chronic inflammatory diseases including asthma, allergy, as well as cancer. Increasing evidence have demonstrated a crucial role of Th2 cells in orchestrating the progress and metastasis of tumors. 353 In addition, Th2 cells and their cytokines were shown to construct an inflammatory TME involving M2-TAMs and promote tumor metastasis in breast cancer. 354 For example, Th2 cells are known to produce IL-4, IL-5, and IL-13, and hence are able to regulate immunity. High levels of Th2 cell-derived cytokines were detected in tumor sites of patients with breast cancer, with the levels of IL-4 and the amount of tumor-infiltrating CD4 + T cells being positively correlated with tumor progression, as well as with metastasis to sentinel lymph nodes, 15 , 355 , 356 highlighting the clinical relevance of Th2 cells in the pathogenesis of breast tumors. Through the secretion of IL-4, Th2 cells were also shown to regulate the polarization and function of M2 macrophages in the TME. Th17 cells are a specific subset of T-helper lymphocytes characterized by the high production of IL-17. Th17 cells have been associated with tumor prognosis. More specifically, Th17 cells have been reported to promote tumor growth by inducing angiogenesis and exerting immunosuppressive functions. In contrast, Th17 cells were also demonstrated to recruit immune cells into tumors, activate effector CD8 + T cells, directly convert them toward the Th1 phenotype, and produce IFN-γ to kill tumor cells. 357 Moreover, specific IL-17 + γδT-cell subsets were observed to play an unexpected role in driving tumor development and progression. 358 They induce an immunosuppressive microenvironment and promote angiogenesis by producing various cytokines as regulatory Th17/Treg/Th2-like cells. 358 Moreover, these pro-tumoral IL-17+γδ-T cells can suppress the maturation and function of DCs and subsequently inhibit the anti-tumor adaptive immunity by the PD-1/PD-L1 pathway. 358 – 360 Studies have revealed that Treg cells could inhibit the maturation of DCs, as well as block the phagocytosis of tumor cells and the expansion of CTLs, which leads to immune surveillance and tumor progression. 361 Treg cells were shown to promote the development and progression of tumors by inhibiting the anti-tumor immunity in TME. In particular, Treg cells were reported to lead to immune suppression by inhibiting co-stimulatory signals by CD80 and CD86 through the cytotoxic T-lymphocyte antigen-4 (CTLA-4), secreting inhibitory cytokines, and directly killing effector T cells. 362 Treg cells have been shown to be chemoattracted to the TME by chemokines, such as chemokine receptors (CCR4)-CCL17/22 and CXCR3-CCL9/10/11, where they are activated to inhibit anti-tumor immune responses. 363 Indeed, a high accumulation of Treg cells in various types of cancer is associated with poor survival. 364 Regulatory B (Breg) cells represent a subset of B cells with immunosuppressive properties. 365 According to the expression of tumor surface markers, the production of soluble factors, and the characteristics of promoting tumor growth, a variety of human and animal tumors of the Breg subtype have been identified. Although the phenotypic markers of different tumors have been reported to be different, the typical phenotypes of both human and mouse were shown to be concentrated in memory CD27 + and transitional CD38 + B cells, exhibiting the same phenotype as plasma cells (e.g., IgA + CD138 + and IgM + CD147 + ). 366 , 367 In both human and mouse studies, Breg cells were observed to exhibit their specific immunosuppressive effects through the secretion of cytokines, such as IL-10 and TGF-β, or through the upregulation of immunomodulatory ligands, such as PD-L1 and CTLA-4, which could attenuate the response of T and NK cells and enhance the pro-tumor effect of Treg cells, MDSCs, and TAMs. 368

Similar to APCs, macrophages and DCs also bridge innate and specific immunity. 249 , 352 , 415 They can recognize tumor cell antigens and present them to the specialized members of the immune system to activate tumor-specific T cells for the killing and clearance of tumor cells. Adaptive immunity plays the most important role in the anti-tumor immune response. 416 It has been noted that CD4 + Th1 cells, activated CD8 + T cells, and γδT cells are often involved in immune responses and have been associated with favorable prognosis in patients with lung cancer. 417 In particular, CTLs are known to recognize the abnormal antigens of tumor cells, secrete granzyme and perforin to kill tumors, and express Fas-L, allowing them to bind with tumor cells to promote their apoptosis. Therapeutic reinvigoration with tumor-specific T cells has greatly improved the clinical outcome in many cancers. Nevertheless, many patients did not achieve a durable benefit. Recent evidence from studies in murine and human cancer have suggested that intratumoral T cells display a broad spectrum of dysfunctional states, shaped by the multifaceted suppressive signals occurring within the TME. 418 However, this dysfunction of T cells in cancer might be utilized to develop personalized strategies to restore anti-tumor immunity. One such example is helper T cells that secrete cytokines, recruit, and activate CTLs to kill tumor cells. 419 Th1 cells, a lineage of CD4 + effector T cells characterized by the secretion of IL-2, IFN-γ, TNF-α, and lymphotoxin are principally responsible for activating and regulating the development and persistence of CTLs. For example, Th1 cells have been shown to release IFN-γ, which stimulates the upregulation of molecules, such as LMP2, LMP7, MECL, PA28, and MHC class I in APCs, all of which contribute to increased antigen presentation to CTLs. 420 Besides, Th1 cells are also known to recruit and activate inflammatory cells (macrophages, DCs, eosinophils, and NK cells) in the tumor, thereby enhancing their ability to eliminate intracellular microbes and to present antigens to CD8 + CTLs. 421 In addition, Th1 cells were also found to directly destroy tumor cells via the release of cytokines, such as lymphotoxin, which activate death receptors on the surface of cancer cells. 422 Furthermore, Th1 cells can directly interact with tumor cells through MHC class II molecules. 423 B cells and humoral immunity have also been described to regulate anti-tumor immunity through other mechanisms, either by expressing cytokines, such as IL-10 or IL-35, inducing antibody-mediated cytotoxicity through NK cells, or by activating the C5a or C3a complement system components, which seem to either activate or suppress anti-tumor immunity in a context-dependent manner. 424 However, the ways by which different B-cell types manifest their immunosuppressive effects remain poorly understood. Some studies have shown that B cells might play a pro-tumor role due to their immunosuppressive subtypes. For instance, tumor-infiltrating B-lymphocytes (TIBs) have been detected in all stages of lung cancer. 425 The existence of TIBs has been reported to vary in different stages and histological subtypes, suggesting a critical role for B cells during lung cancer progression. 426 Of interest, activated B cells were also found to be able to directly lyse tumor cells. Moreover, TIBs have been shown to possess cytotoxicity toward hepatoma cells through the secretion of granzyme B and TRAIL. In one such study, IFN-α- and TLR agonist-stimulated B cells produced functional TRAIL that was cytotoxic to melanoma cell lines. 366 Abundant studies have assessed the function of TIL-B by immunohistochemical examination of CD20. 427 Accordingly, 50.0% of these studies reported a positive prognostic effect for CD20 + TIBs, whereas the rest showed neutral and negative effects. The prognostic significance of TIBs was basically reported to be consistent with that of CD3 + and CD8 + T cells, with the anti-tumor activity of T cells being generally shown to be more potent in the presence of TIB cells. 428 Finally, accumulating evidence have supported a positive role for TIB in anti-tumor immunity, 427 , 429 , 430 suggesting that enhancement of these responses should be considered in future cancer immunotherapies.

Chronic inflammation is considered to be one of the characteristics of tumor initiation and progression, 5 and therapy-induced chronic inflammation often endows residual cancer cells with resistance to subsequent courses of treatment (e.g., chemotherapy resistance and radiotherapy resistance). 4 Anti-inflammatory drugs have been proven efficient for the prevention and treatment of tumors. However, the side-effects of ICB and CAR-T therapies, such as coagulopathy and the “cytokine storm” have limited their full application to cancer therapy, 29 , 30 indicating that reduction of these pernicious inflammation reactions accompanying immunotherapy will improve therapeutic efficacy. Recently, a number of therapeutic strategies to limit inflammatory cells and their products have been successfully applied in clinical or preclinical tumor models. For instance, statins significantly reduced the risk of development of multiple types of cancer by exerting anti-inflammatory and other effects. 21 – 23 Similarly, neutralization of IL-17A, IL-11, or IL-22 could inhibit colonic tumorigenesis at an early stage, 460 – 462 while COXs inhibitors (e.g., celecoxib and aspirin) impaired tumor growth and metastasis. 463 Nevertheless, not all inflammatory diseases or persistent infections are associated with increased cancer risk. Some cases of inflammation, such as allergic diseases that display a state of constant or recurring inflammation, might be even inversely correlated with cancer progression. 464 , 465 In addition, although ICB has been reported to be clinically effective in presenting a durable response to treatment in some solid tumors, most patients with cancer did not respond to treatment for a variety of reasons. Infiltrated-inflamed tumors are considered “hot” tumors containing a high number of infiltrating cytotoxic lymphocytes expressing PD-1 that usually respond well to ICB. 466 In contrast, infiltration-excluded tumors are characterized by the accumulation of CTLs along the border of the tumor mass and a lack of infiltrating CTLs into the tumor core. These tumors are generally considered “cold” tumors with poor sensitivity to ICB. 467 Several promising strategies have been suggested to enhance the inflammatory infiltration that would contribute to the alteration of a cold into a “hot” tumor, thus rendering it sensitive to ICB. 16 Herein, we discuss the targeted therapeutic approaches for the regulation of cancer-related inflammation (Fig. 4 ). Fig. 4 Harnessing the inflammation in cancer therapy. Several promising strategies for regulation of cancer-related inflammation have been suggested to improve anti-tumor response. On the one hand, inducing inflammation and modulating immune cell activation would overcome T-cell exclusion, turning “cold” tumors into “hot” tumors, for instance, local inflammation induced by irradiation or oncolytic viruses can promote innate immunity by activating nucleic-acid-sensing cytosolic receptors (cGAS–STING or RLRs) and subsequent type I IFN response. Besides, promoting DC maturation by cGAS–STING, TLR agonist, DC vaccine, or injection of GM-CSF can induce an acute inflammatory response and priming of T lymphocytes, which facilitate tumor regression. On the other hand, inhibiting chronic inflammation by anti-inflammatory drugs (e.g., aspirin) or accelerating inflammation resolution by proresolving mediators (SPM, e.g., lipoxins, resolvins, protectins, and maresins) also display an overall survival benefit for anti-cancer therapy. Furthermore, limitations of the infiltration and function of immunosuppressive cells (e.g., MDSCs, Treg cells, Breg cells, and M2-TAMs) by blocking inflammatory pathways is another way to restore immune surveillance and promote anti-tumor immunity. Green represents factors that enhancing these cancer-inhibiting inflammation, while red represents factors that blocking these cancer-promoting inflammation, would be beneficial to improve the effect of anti-tumor therapy Non-specific agents targeting chronic inflammation Non-steroidal anti-inflammatory drugs NSAIDs are a family of agents that primarily inhibit the activity of COX enzymes and thereby suppress the synthesis of prostaglandins. Importantly, NSAIDs (including aspirin, celecoxib, and ibuprofen) use has been linked to reduced cancer risk and mortality. 6 Aspirin, one of the most widely used anti-inflammatory drugs, has been identified as a broad-spectrum cancer-preventive agent based on multiple clinical and epidemiological studies. 468 – 470 Besides, both preclinical and clinical studies have demonstrated promising results of the role of celecoxib in the treatment and prevention of cancer, and the best outcomes were observed in colon, breast, prostate, and head and neck cancers. 471 Nevertheless, long-term administration of NSAIDs can result in side-effects including mucosal lesions, bleeding, peptic ulcer, and intestinal inflammation. 20 Thus, the benefits of taking NASIDs for prevention and/or treatm

Corticosteroids, the most effective anti-inflammatory drugs for many chronic inflammatory diseases, are also shown to have anti-cancer activity. 474 For example, pre-treatment with dexamethasone (DEX) improves the efficacy of chemotherapy in xenograft or syngeneic experimental tumor models of glioma, breast cancer, lung cancer, and CRC. 475 Clinical trials have demonstrated that DEX in combination with carfilzomib and lenalidomide, obviously improved progression-free survival of patients with relapsed multiple myeloma. 476 , 477

As discussed above, despite acute inflammation elicited-therapy contributes to destroy cancer cells during treatment, the therapy-elicited chronic inflammation (e.g., IL-1β, IL-6, IL-8, COX2/PGE 2 , NF-κB, and DAMP) plays a pivotal role in promoting therapeutic resistance and cancer progression. 486 , 487 Scientists hypothesized that blocking chronic inflammation might enhance the therapeutic efficacy and benefit to cancer patients. 16 For example, both chemotherapeutic drugs and radiation can induce IL-6 expression in tumor and stromal cells 452 , 453 through the activation of NF-κB signaling, causing therapeutic resistance. 488 , 489 These evidences suggest that blocking IL-6 or it’s downstream signaling pathways may provide therapeutic enhancement. Nowadays, several trials designed to evaluate the efficacy of Tocilizumab (human IL-6R-specific antibody) in chemotherapy are ongoing (Table 1 ). Table 1 Agents targeting cancer-associated inflammation signaling pathways in ongoing or completed clinical trials Drug name Target Condition Phase NCT number Current status Non-specific agents Asprin COX-1/2 Gastric cancer III NCT04214990 Recruiting Cancer-associated thrombosis in solid tumor I NCT02285738 Completed Multiple myeloma II NCT01215344 Completed Colon cancer III NCT02467582 Recruiting Celecoxib COX-2 Primary breast cancer III NCT02429427 Completed Locally advanced NSCLC I NCT00046839 Completed Lung cancer II NCT00020878 Completed Stage II, III, and I breast cancer II NCT00201773 Completed Prostate cancer II NCT01220973 Completed Metastatic colorectal cancer II NCT00466505 Completed Head and neck cancer I NCT00581971 Completed Head and neck cancer II NCT00061906 Completed Metastatic kidney cancer II NCT01158534 Completed Cervical intraepithelial neoplasia II NCT00081263 Completed Colorectal cancer II NCT00033371 Completed Mouth neoplasms II NCT00953849 Completed Malignant peritoneal mesothelioma II NCT02151448 Completed Anaplastic glioma II NCT00504660 Completed Multiple myeloma II NCT00099047 Completed Liver cancer III NCT03059238 Completed Rosuvastatin HMG-CoA Breast cancer II NCT01299038 Completed NSCLC I NCT02317016 Completed Advanced solid malignant tumors I NCT02106845 Completed Ovarian cancer II NCT03532139 Recruiting Rectal cancer II NCT02569645 Recruiting Squamous cell carcinoma I NCT00966472 Completed Endometrial carcinoma II NCT04491643 Recruiting Leukemia, myeloid, acute I NCT03720366 Recruiting Dexamethasone Undefined Prostate cancer II NCT01036594 Completed Ovarian cancer IV NCT00817479 Completed Early-stage breast cancer IV NCT03348696 Completed Lung cancer III NCT00403065 Completed Hepatic cancer II NCT00587067 Completed Brain tumor III NCT00088166 Completed Cytokines and chemokines Infliximab Chimeric TNFα- antibody Pancreatic neoplasms II NCT00060502 Completed Lung neoplasm malignant IV NCT04036721 Recruiting Melanom II NCT04305145 Recruiting Hepatosplenic T-cell lymphoma IV NCT01804166 Completed Renal cell carcinoma IV NCT02596035 Active, not recruiting Etanercept Human TNFR2–Fc fusion protein Pancreatic neoplasms II NCT00201838 Completed Melanoma VI NCT01053819 Completed Metastatic castration-resistant prostate cancer I NCT03792841 Recruiting Leukemia II NCT00509600 Completed Tocilizumab Human IL-6R-specific antibody Urothelial carcinoma I/II NCT03869190 Recruiting Breast cancer I NCT03135171 Recruiting Pancreatic carcinoma II NCT02767557 Recruiting Advanced liver cancers I/II NCT04524871 Recruiting Hematologic malignancy II NCT04395222 Recruiting Prostate adenocarcinoma II NCT03821246 Recruiting Colorectal cancer I NCT03866239 Recruiting Non-small-cell lung cancer I/II NCT03337698 Recruiting Diffuse large B-cell lymphoma I/II NCT03677154 Recruiting Siltuximab Chimeric anti-IL-6 antibody Prostate cancer II NCT00433446 Completed Metastatic pancreatic adenocarcinoma I/II NCT04191421 Recruiting Prostatic neoplasms I NCT00401765 Completed Solid tumors I/II NCT00841191 Completed Multiple myeloma II NCT00402181 Completed Myeloma I/II NCT01531998 Completed Metastatic renal cell carcinoma I/II NCT00265135 Completed Lymphoma, non-Hodgkin I NCT00412321 Completed Carlumab Human anti-CCL2 antibody Prostate cancer II NCT00992186 Completed MABp1 human anti-IL-1α antibody Advanced cancers I NCT01021072 Completed Reparixin inhibitor of CXCR1/2 Metastatic breast cancer I NCT02001974 Completed Metastatic breast cancer II NCT02370238 Unknown Plerixafor inhibitor of CXCR4 Metastatic pancreatic cancer II NCT04177810 Recruiting Hematologic neoplasms II NCT00914849 Completed Advanced pancreatic, ovarian and colorectal cancers I NCT02179970 Completed Brain tumors I/II NCT01288573 Completed Multiple myeloma II NCT01753453 Completed Hematological malignancies I/II NCT00241358 Completed Advanced cancer I NCT03240861 Recruiting Acute myeloid leukemia I NCT00990054 Completed Non-Hodgkin’s lymphoma VI NCT01164475 Completed Anakinra human recombinant IL-1 receptor antagonist Multiple myeloma and plasma cell neoplasm

DCs are specific APCs that function as messengers between innate and adaptive immune responses. 370 However, tumor cells have been shown to hijack DCs to promote chronic inflammation and prevent TAA presentation, thus accelerating tumor development. 526 , 527 Nowadays, modulating the function of DCs to improve cancer immunotherapy is of particular interest. 383 The maturation of DCs is essential for providing co-stimulatory signals to T cells. However, although the maturation of DCs occurs within TME, it is often insufficient to induce robust immunity. 384 Bypassing suppressive pathways or directly activating DCs could trigger a T-cell response, and as such, therapeutic targeting of DCs holds translational potential in combinatorial approaches. The maturation of DCs is important for the initiation of Ag-specific T-cell responses. Nevertheless, the TME also contain a network of immunosuppressive factors (e.g., IL-6, M-CSF, PGE 2 , and VEGF) that could inhibit the infiltration of DCs and subdue their anti-tumor activity. 527 Therefore, targeting these immunosuppressive pathways might improve the recruitment, infiltration, and anti-tumor activity of DCs in the TME. For instance, VEGF, correlated with poor prognosis in patients with different types of cancer, was found to inhibit the differentiation and maturation of DCs via the activation of VEGFR-1 and VEGFR-2. 528 , 529 Moreover, blockade of the VEGF signaling significantly increased the proportion of mature DCs in patients with cancer; as a result, the inhibition of VEGF pathways has become an appreciated approach for the treatment of cancer. 530 In addition, high levels of IL-6, known as a pro-inflammatory cytokine, were associated with a functional defect in DCs from patients with cancer. 531 The IL-6-induced suppression of DCs could be intercepted by the AG490 JAK2/STAT3 inhibitor, 487 , 532 indicating that the pro-inflammatory IL-6/JAK/STAT3 signaling pathway is a promising target for cancer immunotherapy. Moreover, due to the elevated levels of PGE 2 and activity of COXs in patients with colon cancer and its correlation with tumor size and patient survival, PGE 2 has been proposed as the principal prostanoid associated with CRC. Furthermore, PGE 2 was reported to be responsible for the reduced differentiation of DCs from CD34 + precursors; 533 and to mediate DC tolerance via the upregulation of the expression of indoleamine 2,3-deoxygenase (IDO1) in DCs, resulting in the differentiation of Treg cells and the inhibition of antigen-specific stimulatory potential of DCs. 525 In addition, tumor-derived CSF-1 could inhibit the differentiation of hematopoietic progenitor CD34 + cells into DCs and induce the differentiation of cord blood monocytes to tolerogenic DCs. 534 Evidence has shown that the regulation of DCs differentiation driven by CSF-1 was mediated by the PI3K-dependent pathway, delaying the activation of caspases in monocytes. 535 Hence, removing or blocking immunosuppressive factors (e.g . , IL-6, M-CSF, PGE 2 , IL-10, and VEGF) on DCs would promote anti-tumor efficiency by recruiting and promoting the maturation of DCs. To launch a robust antigen-specific anti-tumor response, some immunostimulatory cytokines targeting the activation of DCs are applied in the development of therapeutic vaccines. First, GM-CSF was demonstrated to serve as a potent immune adjuvant inducing long-lasting anti-tumor immunity. 536 Growing evidence have suggested that GM-CSF promotes the activation of DCs and enhances TAA presentation to T cells. 537 In addition, studies revealed that treatment with GM-CSF and IL-4 in vitro could lead to the generation of bone marrow (BM)-derived DCs in mouse and monocyte-derived DCs from human peripheral blood mononuclear cells (PBMC); as a result, these findings have accelerated the clinical applications of GM-CSF. 538 However, it was shown that in clinical trials administration of a high dose of GM-CSF resulted in immunosuppression, indicating a more complex role of GM-CSF in cancer immunotherapy. 539 , 540 Second, the cytokine Fms-related tyrosine kinase 3 ligand (FLT3L), activating signaling through its FLT3 receptor expressed on DC precursors, was observed to be essential during the development of DCs. 541 Culturing mouse BM precursors with recombinant FLT3L (rFLT3L) was sufficient to generate DCs in vitro. 542 Furthermore, administration of rFLT3L in mice resulted in significant expansion of conventional DCs and plasmacytoid pre-DCs in vivo, 543 whereas genetic ablation of FLT3L caused a marked decrease in these subsets. 544 , 545 Typically, DCs can recognize a wide range of “danger signals” from both invading microbes and injured host cells through binding either PAMPs or DAMPs to specialized PRRs, such as TLRs, c-type lectin receptors, stimulator of interferon gene (STING), NOD-like receptors, and the RIG-I and MDA5 DNA/RNA receptors. 370 Accumulating evidence has indicated that activating certain innate immune signaling pathw

MDSCs represent a heterogeneous population of immature myeloid cells with anti-inflammatory effects and potent immunosuppressive activity that play a crucial role in TME. 348 The accumulation and activation of MDSCs have been shown to correlate with tumor progression, metastasis, and recurrence of many types of tumors. 636 Moreover, the efficacy of immunotherapy was negatively correlated with an increased density and activity of MDSCs. 637 , 638 Hence, targeting MDSCs could become a promising approach to overcome tumor-mediated immunosuppression and enhance the efficiency of tumor immunotherapies. The modulation of MDSCs was achieved by facilitating their differentiation into mature myeloid cells, thus inhibiting their development, expansion, and function, as well as depleting their numbers. As the immune suppressive phenotype of MDSCs is known to depend on their immature state, 348 forcing their differentiation into mature myeloid cells (e.g., DCs or macrophages) would impair their suppressive function. It has been demonstrated that agents that can induce the differentiation of MDSCs include vitamin A and D, all-trans retinoic acid (ATRA), IL-12, the activation of TLR9, taxanes, beta-glucan particles, the inhibition of tumor-derived exosomes, and very small size proteoliposomes. 639 – 641 Although the mechanism remains unclear, vitamins A and D have been demonstrated to promote the differentiation of MDSCs into mature cells. Compared with vitamin A-replete mice, vitamin A-deficient mice exhibited increased numbers of MDSCs in bone marrow, spleen, and peripheral blood. 642 Similar results were also observed in tumor-bearing mice and patients with NSCLC. 643 , 644 Furthermore, administration of high dose vitamin D reduced the numbers of immature myeloid cells, and increased the levels of IL-12 and IFN-γ, displaying an anti-tumor effect. 645 ATRA, a vitamin A derivative, was reported to lead to the differentiation of MDSCs to DCs and macrophages by blocking the transduction of the retinoic acid signal in both patients with cancer and tumor-bearing mice. 639 , 646 Mechanistically, administration of ATRA led to reduction in the levels of ROS in MDSCs by activating the ERK1/2 pathway. 647 In addition, in vivo administration of ATRA notably reduced the number of MDSCs, whereas concomitantly boosting CD4 + and CD8 + T-cell-mediated tumor-specific immune responses. Depletion of MDSCs using ATRA in patients with small-cell lung cancer, dramatically enhanced the efficiency of a DC vaccine against p53 by increasing the levels of CD8 + T cells. 648 In a phase I/II study, ATRA was demonstrated to significantly decrease the immunosuppressive function of MDSCs and increase the levels of CD8 + T cells in patients with melanoma receiving ipilimumab therapy compared with patients receiving ipilimumab alone. 649 Taxanes (e.g., docetaxel and paclitaxel), a class of chemotherapeutic drugs, were also reported to facilitate the differentiation of MDSCs in mice and humans with cancer. 650 , 651 Administration of docetaxel reduced the number of MDSCs, decreased their function, whereas increased the activity of CD8 + T cells in tumor-bearing mice. 652 Low-dose paclitaxel promoted the differentiation of MDSCs toward DCs in vitro in a TLR4-independent manner. 653 In a phase II study, women with HER-2 negative breast cancer treated with doxorubicin and cyclophosphamide followed with docetaxel displayed a complete response and lower levels of circulating MDSCs. 654 Besides, treatment with β-glucan has been reported to lead to the maturation of M-MDSCs in vitro, and the suppression of the activity of M-MDSCs in tumor-bearing mice, thereby leading to delayed tumor progression. 655 To date, there have been several ongoing or completed clinical trials evaluating the effects of β-glucans on cancer therapy. 656 Moreover, tumor-derived exosomes, enriched in proteins and nucleic acids, were observed to prevent immature bone marrow myeloid cells from becoming mature DCs. 657 Inhibiting the production of exosomes using dimethyl amiloride heightened the anti-tumor efficacy of cyclophosphamide in vivo. 658 Furthermore, very small size proteoliposomes, such as nanosized particles formed from the outer membrane vesicles of Neisseria meningitidis and GM3 ganglioside, were found to induce the maturation of DCs and an anti-tumor response from CD8 + T cells in mice. 659 These studies indicated that inducing the differentiation of MDSCs in patients with cancer might augment immunotherapeutic approaches. The expansion and infiltration of MDSCs depend on several signaling pathways, including JAK/STAT, VEGF, CXCR2, and COX2/PGE 2 . 660 First, STAT3 is the main transcription factor regulating the immunosuppressive activity of myeloid cells, and blockage of the STAT3 pathway by various inhibitors can decrease the number of G-MDSCs. For example, the herb derivative curcumin, which is a regulator of STAT3 signaling, was found to exhibit several pharmacologic eff

Recent studies have highlighted the fact that patients with low cytotoxic activity of NK cells have a higher incidence of cancer, indicating that NK cells interfere with tumorigenesis. 729 NK cells show cytotoxicity against diverse tumor cell types, but in the TME, Treg cells, M2 macrophages, and MDSCs can inhibit the activation and anti-tumor activity of NK cells through a series of mechanisms, such as the secretion of immunosuppressive products or interfering with the complex receptor array. 730 For example, activated platelets can directly inhibit NK cells, while cytokines and metabolites, including TGF-β, adenosine, PGE 2 , IDO, and others, can directly suppress the maturation, proliferation, and function of NK cells. 400 , 730 Some clinical responses to activating T-cell cytotoxicity immunotherapy, antibody-based, and tyrosine kinase inhibitor-based immunotherapy were shown to positively correlate with the activation of NK cells. 731 , 732 Generally, overcoming the immunosuppressive TME to restore the function of NK cells is a potential therapeutic option for cancer treatment. NK cells express a broad variety of activating and inhibitory receptors, which can be targeted by antibodies and soluble ligands to enhance the activity of NK cells. 733 During infection, the activation of NK cells has been shown to be triggered by multiple pro-inflammatory cytokines, such as IL-2, IL-12, IL-15, IL-18, type I-IFN (IFN-α and IFN-β), and IFN-γ. IL-15 plays an essential role in the regulation of the development and activation of NK cells. 734 In patients with non-Hodgkin’s lymphomas, high concentrations of serum IL-15 following autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) were associated with better survival. 735 In addition, systemic administration of recombinant IL-15 could stimulate the activity of NK cells. In a phase I clinical trial of patients with metastatic malignancies, administration of recombinant IL-15 induced the proliferation of NK cells and substantially increased their numbers. 736 In addition, following haploidentical stem cell transplantation, the IL-15-stimulated infusion of NK cells was shown to induce a clinical response in 4 of 6 patients with pediatric solid refractory tumors. 737 Furthermore, exposure to IL-2 stimulated signaling from activating receptors of NK cells. A phase I clinical trial evaluating rituximab combined with IL-2 against B-cell non-Hodgkin’s lymphoma, revealed that addition of IL-2 to rituximab therapy was safe and resulted in NK cell accumulation and ADCC activity that correlated with the better responses. 738 Type I IFN could also preactivate NK cells by activating their receptors. Cyclic GMP-AMP, a second-messenger was reported to activate the STING adaptor protein, stimulating the production of IFN-β, and resulting in the priming of NK cells for cytotoxicity. 739 Furthermore, oncolytic viruses are known to be able to trigger the recruitment of immune cells and induce anti-cancer responses by activating NK cells and T cells, thus selectively killing cancer cells. 740 , 741 In preclinical models, localized therapy using the oncolytic Newcastle disease virus (NDV) induced inflammatory immune infiltrates in distant tumors, making them susceptible to ICB immunotherapy through the activation of NK and T cells. 742 Disruption of immunosuppression is another strategy to elicit NK cells in the TME. The inhibitory factors of solid tumors are known to be composed by a complex composition of immunosuppressive molecules, such as TGF-β, IL-10, IDO, PGE 2 , VEGF, iNOS, and ROS, produced by regulatory immune cells, such as Treg cells, MDSCs, and M2-TAMs, as well as by tumor cells themselves. 730 These factors generate a chronic inflammatory and immunosuppressive TME, accelerating tumor progression. Besides, the PD-1 and CTLA-4 immune checkpoints, lymphocyte activation gene 3 protein (LAG3), and T-cell immunoglobulin mucin-3 (TIM3) are expressed in some types of NK cells, with their ligands potentially taking part in dampening NK anti-tumor responses; as a result, blockade of interaction with checkpoint inhibitors boosts the activity of NK cells. 743 – 745 Killer cell immunoglobulin-like receptors (KIRs) are the most polymorphic among inhibitory receptors that bind the human leukocyte antigen (HLA) class I receptors. As such, blockage of KIRs using an anti-KIR blocking antibody (lirilumab) is currently tested in clinical trials. 746 It has been reported that inhibition of the TAM tyrosine kinase receptors (e.g., Tyro3, Axl, and Mer) in NK cells can enhance the antimetastatic potential of NK cells in murine models. 747 In humans, CD96 is known to be mainly expressed in NK cells, CD8 + , and CD4 + T cells. Accordingly, Cd96 (−/−) mice displayed hyperinflammatory responses to LPS and resistance to 3′-methylcholanthrene (MCA)-induced carcinogenesis and lung metastases. Importantly, blockade of Cd96 using an anti-Cd96 antibody or gene knockout improved the fu

Activated adaptive immune cells, including T and B lymphocytes, are known to further amplify the initial inflammatory response. 769 More specifically, Th1 cells activate macrophages both through cell-to-cell contact and secretion of IFN-γ, 770 while Th2 cells activate eosinophils through the release of cytokines, and B cells secrete antibodies that activate the complement cascade, as well as phagocytes, NK cells, and mast cells through Fc receptors. 351 , 771 , 772 However, certain adaptive immune cells, especially Treg cells and Breg cells have been found to be able to turn off the inflammatory response. 773 , 774 Thus, activating acquired immunity is a promising new target for cancer immunotherapy and inflammation control. Activating cytotoxic T cells During the inflammation process, activated CD8 + T cells produce IFN-γ, TNF-α, and granzymes, which destroy target cells. 775 Clinical evidence have shown that the number of TILs, particularly CD8 + T cells, is a positive prognostic marker of multiple solid tumors. 776 However, the effector functions of CD8 + T cells have been shown to be gradually lost in TME during chronic inflammation, a condition named T-cell exhaustion. 418 T-cell exhaustion, in which reduced and dysfunctional effector T cells lead to immune escape, is one of the mechanisms employed by pathogens or tumor cells to get rid of the control of immunologic surveillance. 418 Currently, exogenous reactivation, or priming of CTLs has been demonstrated to overcome the chronic inflammatory TME, leading to successful immunotherapy strategies against cancer. It is well known that cGAS–STING-mediated DNA sensing in cancer cells or phagocytes (e.g., DCs, macrophages) is crucial for detecting cytosolic DNA, inducing a type I-IFN response for augmenting anti-tumor immunity, as well as host defense against pathogens. 777 It has been reported that once activated by ligands, STING aggregates in a perinuclear region and activates the TBK1 kinase, which in turn phosphorylates IRF3, directly launching the transcription of type I IFN genes. Evidence has shown that the STING agonist DMXAA induces a cooperation between T lymphocytes and myeloid cells, resulting in tumor regression in vivo. 778 Besides, co-stimulatory and co-inhibitory receptors play a crucial role in T-cell biology, as they are known to determine the functional outcome of TCR signaling. Accumulative evidence have suggested that CD40 plays an intrinsic role in the co-stimulation of T cells. 779 CD40 has been shown to activate multiple signaling pathways, including Ras, PI3K, and protein kinase C, resulting in NF-κB-dependent induction of cytotoxic mediators (e.g., granzyme and perforin), and boosting of CD8 + T cells. 780 CD28, another major co-stimulatory molecule for the priming of T cells, was reported to recruit adaptors, such as PI3K, growth factor receptor-bound protein 2 (GRB2), and LCK, resulting in the activation of nuclear factor of activated T cells (NFAT), activator protein (AP)-1, and NF-κB. 781 The CD28 signaling was further shown to amplify TCR signaling, including the expression of IL-2 and B-cell lymphoma (Bcl)-2, modulation of metabolism, and epigenetic changes. 781 , 782 Nowadays, a substantial amount of drugs targeting co-stimulatory molecules are in clinical trials against cancer, including members of the TNF receptor superfamily, OX40 (CD134), CD27, and 4-1BB (CD137). 783 One of the primary characteristics of exhaustion is the co-expression of high levels of a series of inhibitory receptors, including PD-1, CTLA-4, CD152, LAG-3, Tim-3, CD244/2B4, CD160, and TIGIT. Importantly, ICB has been found to be able to induce durable responses among multiple types of cancer both in patients and murine model. 784 Two inhibitory molecules, the cytotoxic CTLA-4 and PD-1, have attracted much attention, because blockage of the CTLA-4 or PD-1 signaling has prominently improved the survival of patients with metastatic solid cancers. 785 Furthermore, ICB alone or combinations with other immunotherapies, such as adoptive cell therapy and DC vaccination, has displayed some survival benefit for patients with advanced cancer. 785 In the perspective of anti-tumor immunotherapy, modulating the actions of cytokines is an attractive strategy to control exhausted CD8 + T cells. For example, administration of IL-2 has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic RCC and melanoma. 786 Moreover, establishing the effective combination of cytokine-targeted therapy and ICB is of great interest. Administration of IL-2 during chronic viral infection was demonstrated to exhibit striking synergistic effects with PD-1 blockade, thus enhancing virus-specific CD8 + T cells. 787 The synergy of exogenous IL-2, PD-1 blockade, and a powerful T-cell vaccine combination therapy has been confirmed in a cancer model. 788 Besides, blockade of IL-10R significantly improved the efficacy of anti-PD-L1 treatment, resulting in enh

The malfunction of Th1 cells has been observed in the peripheral blood of multiple types of cancer, involving them in tumorigenesis and tumor progression. 840 Furthermore, a high density of tumor-infiltrating Th1 cells is considered to be a beneficial prognostic marker in several types of solid cancers, including OVC, CRC, NSCLC, and breast cancer. 841 , 842 Clinical trials have demonstrated that inflammation driven by tumor-specific Th1 cells prevented the progression of malignancies, 843 providing a strong rationale to develop anti-tumor Th1 immunity-activating immunotherapy. An efficient strategy to stimulate the Th1 response is using a cancer vaccine. In phase I/II trials of patients with NSCLC, a human telomerase reverse transcriptase (hTERT)-derived helper peptide vaccine (GV1001) induced CD4 + T cells displaying a Th1 cytokine profile, and stimulated T-cell responses in >50% of subjects, without exhibiting clinically important toxicity. 844 , 845 These results indicated a positive correlation between GV1001-specific Th1 responses and prolonged survival. Recently, universal cancer peptides (UCP), novel anti-tumor Th1-inducer peptides derived from hTERT, were demonstrated to induce a spontaneous CD4 T-cell response in 38% of patients with metastatic NSCLC, with the high-avidity UCP-specific CD4 T cells being Th1 polarized. 846 In addition, tumor cell loaded type-1 polarized DCs induced the activation of antigen-specific Th1-type CD4 + T cells, resulting in a significant reduction in tumor growth. 847 Application of Th1 cytokines has been suggested to reinforce the anti-tumor effects of immunotherapy. Th1-type cytokines, including IL-1, IL-2, IL-12, and GM-CSF are known potent stimulators of the differentiation of Th1 cells and Th1-based anti-tumor response. 848 Although many preclinical studies have demonstrated the anti-tumor effects of Th1 cytokines, their clinical efficacy remains limited. To date, most studies on cytokine immunotherapy have focused on the mechanism by which to augment the Th1 response. To this end, many studies have combined cytokine-based therapy with other therapies to reverse immunosuppression in TME. 849 For instance, IL-12 was found to promote the differentiation of Th1 cells and activation of NK cells, as well as increase the production of IFN-γ. More specifically, IL-12 induced Th1 responses against cancers and improved the anti-tumor efficacy of cancer vaccines, DC vaccines, and other cytokines (IL-18 and IL-15). 849 Besides, IL-12 gene-modified DCs showed positive clinical response in patients with stage IV melanoma. 850 Many immune adjuvants are known to display potent capability toward enhancing the production of Th1 cytokines and amplifying Th-immunity in response to cancer vaccines. Currently, several important Th1 adjuvants have been used for the activation of Th1 immunity, such as Bacillus Calmette-Guérin (BCG), heat-shock proteins (HSPs), TLR9 agonists, and unmethylated cytosine phophateguanosine oligodeoxynucleotides (CpG-ODN). 848 Evidence has shown that PGE 2 shifts the balance away from Th1 responses toward Th2 responses. 851 Overproduction of PGE 2 has been observed in multiple Th2-associated diseases, including atopic dermatitis and asthma. 852 Moreover, inhibition of prostaglandin synthesis using COX2 inhibitors was reported to cause an augmentation of the Th1 response, 853 suggesting that reducing the production of PGE 2 would induce the Th1 response, improving the efficacy of anti-tumor immunotherapy. Therefore, developing strategies focusing on the activation of the Th1 immunity response would contribute to successful anti-tumor immunotherapy.

The IL-17-secreting CD4+ T cells have been defined as Th17 cells, and constitute ~1% of CD4+ T cells in the peripheral blood of healthy donors. 857 Through the secretion of IL-17, IL-17F, and IL-22, Th17 cells play key roles in many human diseases including inflammation, autoimmune diseases, and cancer. Importantly, Th17 cells have been reported in many types of human cancers, impacting the prognosis of patients. For example, high levels of Th17 cells have been associated with improved prognosis of patients with OSCCs, 11 and salivary gland tumors. 858 Patients with melanoma, early-stage OVC, and malignant pleural effusions exhibiting increased numbers of Th17 cells were reported to have better survival. 859 As experimental and clinical studies have demonstrated that targeting IL-17 has achieved great efficacy in autoimmune diseases, such as psoriasis, 860 it is predictable that manipulation of Th17-cell biology would be a promising therapeutic modality for the treatment of Th17-affected cancers. In CRC, however, high levels of IL-17 were observed to refrain Th1-armed anti-tumor immunity, in part by attracting myeloid cells into tumors. Deletion or blockade of IL-17 suppressed the tumor-promoting inflammation, reactivated tumor immunosurveillance, and reduced the frequency of tumorigenesis in lung cancer models. 460 , 861 Accordingly, patients with CRC could be benefited by cancer immunotherapy using the anti-IL-17 approach as adjuvant therapies, which would contribute to the inhibition of both IL-17-mediated tumor promotion and T-cell exclusion. Furthermore, the development and function of Th17 cells have been shown to be regulated by innate system-derived pro-inflammatory cytokines, such as IL-6, IL-23, and IL-1. In particular, IL-23 promotes inflammatory responses, such as the upregulation of the MMP9 matrix metalloprotease, and increases angiogenesis, but reduces the infiltration of CD8 T cells. 862 , 863 As a result, transplanted tumors were observed to be growth-restricted in IL-23R-deficient mice. 864 Besides, IL-6 has been shown to stimulate the production of Th2 type cytokines and upregulate the expression of VEGF and NRP-1 in pancreatic cancer cells. 865 Agents targeting IL-6, IL-6 receptor, or JAKs have already received U.S. FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms. Moreover, to reduce the adverse effects of CAR-T cells, combinations with anti-IL-6/IL-6R signaling strategies are being currently evaluated in patients with hematopoietic malignancies and solid tumors. 487 , 866

In human cancer, the frequencies of regulatory B (Breg) cells have been shown to usually increase with tumor progression, and to be enriched in tumors compared with peripheral blood or adjacent normal tissues. Breg cells are known to mediate inflammation and maintain homeostasis mainly via the secretion of anti-inflammatory cytokines, such as IL-10, TGF-β, and IL-35, 881 directly killing effector cells by expressing Fas-L. 882 Through the secretion of TGF-β, Breg cells were reported to promote the transformation of effector CD4 + T cells to active Tregs, which in turn suppressed the proliferation of T cells and facilitated tumor metastasis. 883 Moreover, IL-21 was shown to induce granzyme B (GrB) + Breg cells contributing to tumor escape from an efficient anti-tumor immune response. 884 In addition, Breg cells were observed to dampen immune responses through the inhibition of the differentiation of DCs and the proliferation of Th1 and Th17 cells. 885 These results suggested that Breg cells play an important role in regulating inflammation and the immunosuppressive TME, which prevent the anti-tumor immune process. LXA 4 , an endogenous eicosanoid derived from AA, has been highlighted in the regulation of inflammation. 886 Evidence have shown that LXA 4 repressed the generation of Breg cells by dephosphorylating both STAT3 and ERK, resulting in impaired tumor growth. 26 Targeting Breg cells by LXA 4 decreased the number of Treg cells in tumor tissues, as well as enhanced the activities of cytotoxic T cells. 26 These findings revealed that targeting Breg cells through the administration of LXA 4 could have potential clinical applications. Interestingly, another metabolite from this pathway was observed to display the opposing effect: LTB 4 could trigger the conversion of naive B cells into Breg cells. Furthermore, MK886, a 5-lipoxygenase activating protein (FLAP) inhibitor and antagonist of PPARα, could inhibit the generation of Breg cells, suggesting the crucial role of the 5-LOX/FLAP pathway in the differentiation and suppressive function of Breg cells. 887 The phytoalexin resveratrol, which is known to block the phosphorylation of STAT3, was demonstrated to cause a decreased proportion of Breg cells in 4T1-bearing mice, inhibiting the formation of lung metastases. 887 Likewise, total glucosides of paeony (TGP) extracted from plant were found to exert anti-inflammatory and immunomodulatory activities. In a rat model of diethylnitrosamine (DEN)-induced HCC, treatment with TGP resulted in a reduction of nodules and improvement of survival through a reduction in the numbers of Breg cells. 888 Furthermore, tumor-infiltrating Breg cells with increased expression of PD-L1 and TGF-β suppressed the proliferation of CD4 + T cells, CD8 + T cells, and NK cells. Monoclonal antibodies targeting TGF-β or PD-L1 notably suppressed tumor growth and reduced the number of Breg cells in mice. 887 Treatment with ibrutinib was shown to improve the immunosuppressive TME of chronic lymphocytic leukemia (CLL) via the STAT3-mediated suppression of Breg cells and the PD-1/PD-L1 pathway. 889 Taken together, selectively targeting Breg cells in the TME appears to be a hopeful strategy for tumor immunotherapy. Nowadays, numerous trials designed to evaluate the efficacy of inflammation modulators in cancer prevention and treatment are ongoing. Some ongoing or completed clinical trials with agents targeting cancer-associated inflammation signaling pathways are listed in Table 1 . On the one hand, monotherapy with anti-inflammatory agents has been proved limited efficacy in cancer treatment, for example, monotherapy with agents targeting IL-6 only showed moderate activity against solid tumors in non-stratified patients ( NCT00841191 , NCT01531998 ). On the other hand, modulating inflammation can boost anti-cancer efficacy in synergy with chemotherapy or immunotherapies, for example, compared with placebo, adjuvant therapy with the celecoxib can benefit disease free survival (DFS) of two years and overall survival (OS) in primary breast cancer patients received endocrine treatment according to local practice ( NCT02429427 ). Hence, based on the relationship between inflammation and cancer, targeting inflammatory cells or inflammatory factors would contribute to the achievement of better outcomes for cancer therapeutics. The acute inflammation induced by some therapies (e.g., recombination IFN, TLRs activator, STING activator) can redirect the pro-tumor TME toward an anti-tumor immune milieu, which can enhance efficiency of anti-cancer therapies (e.g., chemotherapy, radiotherapy and immunotherapy). Moreover, a number of therapeutic strategies to limit chronic inflammation (incuding systermic and local inflammation) have been successfully applied in clinical or preclinical tumor models to prevent tumorigenesis, or sensitize tumor to anti-cancer therapies including chemotherapy, radiotherapy, and immunotherapy.