Targeting Cancer-promoting Inflammation — Have Antiinflammatory Therapies Come Of Age? Part 2

Mechanisms of anti-inflammatory Therapy

Suppression of oncogenic pathways

Targeting tumour cell-intrinsic pathways.—COX2-PGE2 signalling can directly confer epithelial cells with protumorigenic traits, thus facilitating the development of inflammation-driven cancer (FIG. 2). COX2 can activate the AKT, mTOR and NF-κB pathways to support cancer cell proliferation either directly or via PGE2 signalling. Consistently, aspirin and selective COX2 inhibitors have pro-apoptotic and antiproliferative effects on COX2-overexpressing cancer cells145. In addition, PGE2 silences tumour-suppressor genes by reinforcing their promoter methylation through an EP4–DNA methyltransferase pathway146. 

Correspondingly, combined treatment with celecoxib and decitabine effectively mitigates intestinal tumour development in ApcMin/+ mice146. Moreover, hepatic COX2 overexpression induces spontaneous HCC development in mice by reducing the expression of methylcytosine dioxygenase TET1 (a DNA demethylase), thereby resulting in increased DNA methylation, epigenetic silencing of tumour suppressor genes and in the activation of oncogenic pathways, which can be reversed by celecoxib treatment40. NSAID treatment can also neutralize a senescence-associated inflammatory response that promotes the growth and invasiveness of p53-deficient intestinal cells and thus prevents colorectal carcinogenesis147. 

The formation and growth of tumour cells are partly related to the imbalance of the body's immune system. Therefore, improving the immunity of the body's immune system can prevent and treat tumours. The treatment method targeting tumour cells is to use drugs or vaccines targeting certain molecules to directly act on cancer cells, inhibit their growth and spread, and at the same time cause the host immune system to respond and improve their immunity. Therefore, targeting tumour cells and improving the body's immunity can complement each other to achieve better therapeutic effects. At the same time, we must pay attention to our immunity in our daily life. Cistanche can significantly improve immunity. Meat ash contains a variety of biologically active components, such as polysaccharides, two mushrooms, Huang Li, etc. These components can Stimulate various cells of the immune system and increase their immune activity.

Click health benefits of cistanche

Surprisingly, PGE2 also promotes colon regeneration in preclinical models of colitis through feedforward activation of the transcriptional regulator YAP1, which can trigger tumorigenesis; accordingly, administration of the NSAID indomethacin or an EP4 antagonist exacerbates colitis but can prevent colon tumorigenesis in mice148.

Via competitive inhibition of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, statins can activate the AMPK and p38 MAPK pathways or suppress MYC phosphorylation to induce cell cycle arrest and apoptosis149-151. Similarly, metformin improves insulin sensitivity through the indirect activation of AMPK, which inhibits the activity of mTOR complex 1 (mTORC1), thereby leading to cell growth arrest and resulting in a broad cancer chemopreventive effect152. Metformin can also suppress cyclin D1 expression as well as the inflammatory responses associated with stem cell activation152-154. 

Consistent with the link between diabetes and cancer, hyperglycaemia impairs the AMPKmediated phosphorylation and stabilization of TET2, leading to global DNA demethylation and the inhibition of tumour growth in mice; the anticancer effects of metformin might also depend on the reprogramming of a cancer-favourable epigenome via the activation of this AMPK-TET2 pathway155. Similarly, metformin has been shown to integrate metabolic and epigenetic signalling via an AMPK–SETD2–EZH2 axis, thereby suppressing prostate cancer metastasis156. 

Curiously, metformin impairs tumour growth only if administered during periods of fasting-induced hypoglycaemia in mice157. Mechanistically, the inhibition of CIP2A by metformin together with upregulation of the PP2A B subunit isoform B56δ under low glucose conditions activates GSK3β signalling, which leads to reduced levels of the pro-survival protein MCL1 and, ultimately, cancer cell death157 (FIG. 2).

Targeting tumour cell-extrinsic factors.

Early studies of diethylnitrosamine-induced HCC in mice have shown that IL-1α released by necrotic hepatocytes acts as an inflammatory switch that supports compensatory cell proliferation and HCC development, which could be counteracted using the IL-1R antagonist anakinra158. IL-6 is one of the central orchestrators of the inflammation-cancer interface, which directly enhances the proliferative and metastatic capacities of cancer cells159. Mouse models had revealed the therapeutic potential of drugs that target IL-6 or its receptor but, rather disappointingly, tocilizumab, canakinumab and siltuximab had limited therapeutic activity in patients with cancer cachexia109. 

A novel IL-6 family member, leukaemia inhibitory factor (LIF), has been identified as a key pro-tumour paracrine factor secreted by activated pancreatic stellate cells; LIF blockade using a monoclonal antibody restricted the progression of PDAC in mice and augmented responses to chemotherapy by converting the cancer cells to a less aggressive and more drug-susceptible state9. In human and mouse prostate cancers, IL-23 produced by MDSCs can enhance androgen receptor (AR) activity in cancer cells, thus promoting a castration-resistant phenotype10. Accordingly, an anti-IL-23 antibody reversed resistance to androgen-deprivation therapy in a mouse model of prostate cancer10 .

Receptor activator of nuclear factor-κB (RANK) signalling governs osteoclastogenesis and bone resorption and has been examined as a therapeutic target in patients with breast or prostate cancer bone metastases11. Interestingly, RANK ligand (RANKL)-producing regulatory T cells also promote the spread of RANK-expressing mammary carcinoma cells to the lung in mouse models160. Accordingly, the administration of an antagonistic RANK– Fc fusion protein substantially reduces pulmonary metastasis in these models160. Myeloid cell-derived thymic stromal lymphopoietin promotes the survival of tumour cells through induction of the antiapoptotic molecule BCL-2 and a neutralizing antibody to thymic stromal lymphopoietin inhibits the growth of both primary tumours and lung metastases in mice161. 

CXCR4 is a chemokine receptor commonly expressed by multiple types of tumour cells; its ligand, CXCL12, is a component of the inflammatory TME and can enhance the survival and migration of tumour cells. Systemic administration of the CXCR4 antagonist plerixafor (AMD3100) inhibits the growth of intracranial glioblastoma and medulloblastoma xenografts in mice by reducing activation of the ERK and AKT signalling pathways162. Likewise, CXCR4 inhibition with motixafortide (BL-8040) restricts the growth of mouse neuroblastomas via the tumour-suppressive microRNAs miR-15a and miR-16-1, which silence BCL-2 and cyclin D1 expression163. Integrins, lectins and neuregulins are also known to contribute to the inflammatory TME and might therefore prove to be worthwhile therapeutic targets164-166 if their oncogenic capacities can be inhibited using the corresponding antagonists.

Dietary vitamin D3 and its analogue calcitriol regulate multiple genes by binding to the nuclear vitamin D receptor (VDR), a member of the steroid–thyroid–retinoid receptor superfamily of ligand-activated transcription factors. Theoretically, vitamin D and calcitriol could suppress inflammation, cancer cell proliferation, invasion and metastasis; such anticancer effects have been validated in mouse xenograft models but, unfortunately, have not consistently been demonstrated in humans125.

Disrupting the tumour-supporting stroma

Targeting inflammatory messengers.

Some soluble factors act as envoys by shuttling between the tumour and its stroma, thus constituting important targets for anti-inflammatory treatments (FIG. 3). In the aforementioned diethylnitrosamine-induced model of HCC, excessive production of reactive oxygen species (ROS) by inflammatory stromal cells results in oxidative DNA damage, hepatocyte death and compensatory cell proliferation167. Accordingly, oral administration of the chemical antioxidant butylated hydroxyanisole or vitamin E decreases ROS production and prevents diethylnitrosamine-induced HCC167. 

Similarly, butylated hydroxyanisole attenuates ROS-elicited TNF and IL-1β production by Kupffer cells and can prevent pre-malignant cholangiocellular lesions in mouse models of intrahepatic cholangiocarcinoma168. In addition, the antioxidant N-acetylcysteine prevents ROS-induced T-cell death upon hepatic steatosis and delays HCC development in mice169 (FIG. 3a).

IL-17 is implicated in the pathogenesis of both non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis, including links with liver inflammation, fibrogenesis and carcinogenesis. In mice, targeting IL-17 or its upstream inducer IL-23 markedly suppressed the development of NASH-associated or alcoholic steatohepatitis-associated HCC170,171. Intriguingly, CD4+ T cell-derived IL-17 was found to blunt the anticancer efficacy of chemotherapeutic agents in mice and this effect could be averted by blocking the IL-1βIL-1R pathway172 (FIG. 3b).

Complement component 3 (C3) is upregulated in mouse and human leptomeningeal metastatic cells and can activate C3a receptor (C3aR) signalling in the choroid plexus epithelium, which in turn can alter the composition of the cerebrospinal fluid in a manner that promotes tumour growth173. Correspondingly, a C3aR antagonist is effective in reducing breast and lung cancer leptomeningeal metastases in mice173 (FIG. 3c).

The glycosaminoglycan hyaluronan (HA), a major component of the extracellular matrix, is abundant in the microenvironment of chronic inflammatory diseases as well as in several malignancies. In a genetically engineered mouse model (GEMM) of PDAC, HA has been identified as a crucial modifier of tumour vascular function and enzymatic depletion of HA using PEGylated human recombinant PH20 hyaluronidase (PEGPH20) substantially enhanced drug delivery and therapeutic efficacy with diminished tumour growth174 (FIG. 3d). Unfortunately, however, the addition of PEGPH20 to standard chemotherapy was found to increase drug toxicity and thus to decrease treatment durations in patients with this disease175.

Targeting inflammatory cells.

Macrophages are the dominant orchestrators of cancer-promoting inflammatory signals and an abundance of TAMs is associated with high-grade tumours and a poor prognosis176. The cytokine CSF1 has important roles in regulating macrophage recruitment and function through CSF1R signalling (FIG. 3e).

CSF1R inhibition can specifically deplete TAMs and suppresses glioma progression177 and lung cancer brain metastasis178 in mouse models. Increased CSF1 expression has been observed in patients with prostate cancers treated with radiotherapy or androgen deprivation therapy; in mouse models, this upregulation of CSF1 culminates in acquired treatment resistance, which can be reversed through CSF1R inhibition179,180. In a different model, CSF1R inhibition does not affect mammary tumour growth or metastasis but rather sensitizes the tumours to chemotherapy181. Chemokines and chemokine receptors have been implicated in tumour infiltration by macrophages. Accordingly, antibodies targeting CCL2 or CCL5 impede tumour growth and dissemination in multiple preclinical models176. 

In a mouse model with excessive complement activation, the administration of a complement component C5a anaphylatoxin chemotactic receptor (C5aR) antagonist attenuates macrophage-mediated inflammation and tumorigenesis182. The G protein-coupled receptor 109A (GPR109A) has anti-inflammatory effects on colonic macrophages and dendritic cells (DCs) and is essential for the induction of IL-18 expression in the colonic epithelium; the GPR109A agonists niacin (vitamin B3) and butyrate efficiently suppress inflammation-induced and ApcMin/+ intestinal tumours in mice183.

Neutrophils often accumulate in both primary tumours and pre-metastatic niches in response to diverse inflammatory milieus184. Moreover, the neutrophil-depleting antibody anti-Ly6G effectively prevents tumour cell dissemination to distant organs in mice185 (FIG. 3e). Proinflammatory molecules, such as high mobility group box 1 (HMGB1), IL-1β, IL-17 and G-CSF, help shape the tumour-promoting phenotypes of neutrophils; thus, the neutralization or inhibition of these factors is effective in reducing metastasis in preclinical models186,187. Additionally, pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase or neutrophil extracellular trap-associated signals (the latter using antiCCDC25 antibodies) interferes with the pro-metastatic functions of neutrophils in many settings188-190.

Fibroblasts are typically the most abundant stromal component within solid tumours and these cells can become activated during tissue inflammation and fibrogenesis. As such, cancer-associated fibroblasts (CAFs) are integrally involved in cancer-promoting inflammation. CAF-targeting therapies, including fibroblast activation protein-neutralizing antibodies, CXCL12–CXCR4 pathway antagonists, all-trans retinoic acid, the VDR ligand calcipotriol, and the immunomodulatory and anti-inflammatory agent ursodeoxycholic acid, have demonstrated anticancer activities in preclinical models191,192 (FIG. 3e)

Platelets are hypothesized to promote tumour cell dissemination. For example, platelet accumulation and tumour angiogenesis is markedly inhibited using antiplatelet or antiIL-6 antibodies, which enhances the therapeutic efficacy of paclitaxel in a mouse model of ovarian cancer193. Moreover, suppression of platelet activation and aggregation using aspirin and clopidogrel can abrogate HBV-associated or NASH-associated inflammation and carcinogenesis194,195 (FIG. 3e).

Promotion of antitumour immunity

Using conventional anti-inflammatory drugs.

Mounting evidence from preclinical studies indicates that conventional anti-inflammatory drugs exert immunomodulatory functions (FIG. 3f,g). Notably, COX inhibition synergizes with PD-1 inhibition in eradicating mouse tumours68,196. Mechanistically, tumour-derived PGE2 impairs the natural killer cell-mediated recruitment of conventional type 1 DCs, thus culminating in tumour immune evasion, which could be reversed by treatment with aspirin or celecoxib68,196 (FIG. 3g). Consistent with its immunosuppressive properties, PGE2 produced by senescent hepatic stellate cells directly compromises T cell function in mice with HCC induced by a high-fat diet197. Accordingly, an EP4 antagonist restores antitumour immunity and attenuates HCC development in this model197. PGE2 has also been implicated in the M2 polarization of macrophages198 .

Metformin triggers AMPK activation and consequently silences hypoxia-inducible factor-α, which is a transcription factor crucial in inducing CD39 and CD73 expression on MDSCs; CD39 and CD73 mediate the production of the immunosuppressive factor adenosine; therefore, suppression of the expression of these proteins by metformin reinvigorated the antitumour activity of CD8+ T cells in patients with ovarian cancer199 (FIG. 3g). Interestingly, metformin-induced AMPK activation can directly cause PD-L1 phosphorylation, which results in abnormal glycosylation, endoplasmic reticulum accumulation and endoplasmic reticulum-associated protein degradation, thereby manifesting a potential mechanism for increased T cell activity and, thus, immunotherapy efficacy200 (FIG. 3f). Furthermore, increased infiltration of CD8+ T cells and other immune cells into the TME has been observed in patients with ESCC receiving low-dose metformin201.

The modulation of cholesterol metabolism can also potentiate T cell receptor signalling and prevent T cell exhaustion. Specifically, the disruption of cholesterol esterification using the acyl-CoA cholesterol acyltransferase 1 inhibitor avasimibe potentiates the antitumour effect of PD-1 inhibition in preclinical models202,203. Moreover, conventional anti-platelet agents can improve T cell-based therapy in mouse models in which platelets constrain T cell-mediated anticancer immunity through a glycoprotein A repetitions predominant (GARP)–TGFβ axis204 (FIG. 3g).

Using targeted agents.

Targeted anti-inflammatory agents might also harness the host immune system to fight cancer and many of these agents depend on the manipulation of myeloid cell plasticity (FIG. 3). CSF1R inhibition directly depletes or reprogrammes immunosuppressive TAMs and consequently improves antitumour immune responses in many preclinical models205-208. TAMs can also have an important role in antibody-based cancer therapy through antibody-dependent cellular phagocytosis. Surprisingly, when phagocytosing tumour DNA, TAMs impart immunosuppression through the upregulation of PD-L1 and indoleamine 2,3-dioxygenase (IDO) expression, which is dependent on inflammasome activation and IL-1β production; therefore, treatment with an anti-IL-1β antibody substantially improves the efficacy of anti-HER2 therapy in immunocompetent mice bearing HER2+ breast cancer cells209. 

In another model of breast cancer210, genetic deficiency of IL-1β expression increases the intratumoral DC to macrophage ratio and anti-IL-1β antibodies synergize with anti-PD-1 treatment in tumour elimination. In response to inflammatory stimulation or chemoattraction, CD11b+Gr1+ myeloid cells frequently infiltrate tumour sites and exert an immunosuppressive effect in various mouse models; the pharmacological depletion or segregation of these cells (which are typically referred to as MDSCs) from tumours using an anti-Gr1 antibody or a CXCR1/2 antagonist, respectively, restored antitumour immunity211-214. Notably, the overexpression of IL-1β led to MDSC mobilization and activation in the early stage of gastric carcinogenesis and, therefore, anti-IL-1β therapy might prevent cancer development by stimulating turnover of the immunosuppressive environment of neoplastic tissues215 .

Remarkably, studies using human CRC samples have revealed that inflammatory DCs can induce IL-17-producing γδT (γδT17) cells in an IL-23-dependent manner216. In addition to IL-17, these γδT17 cells also secrete TNF, IL-8 and GM-CSF, all of which can attract MDSCs and sustain their immunosuppressive activity, which is reversible with IL-23 neutralization216 (FIG. 3g). Furthermore, in a GEMM of inflammatory lung cancer, co-blockade of IL-23 and CCL9 abrogated MYC-induced immune exclusion and tumour progression217.

The C5a–C5aR axis contributes to the immunosuppressive effects of myeloid cells. For example, C5a generated locally in the TME can recruit MDSCs and promote their production of ROS and reactive nitrogen species, which hamper the antitumour activity of CD8+ T cells. Preclinically, the pharmacological inhibition or genetic ablation of C5aR impairs tumour growth via increases in the abundance and cytotoxicity of CD8+ T cells218. Furthermore, the C5aR antagonist PMX-53 improves the antitumour efficacy of immunotherapy or chemotherapy in various mouse models219,220. A phase I trial of the C5aR1 monoclonal antibody IPH5401 in combination with the anti-PD-L1 antibody durvalumab in patients with advanced-stage solid tumours is ongoing221 (STELLAR-001; NCT03665129). Phagocytosis checkpoint proteins, such as CD47, are additional novel targets for cancer immunotherapy222 and might provide more opportunities for combinations with anti-inflammatory agents.

In addition to myeloid cells, CAFs, B cells, γδT cells, type 1 innate lymphoid cells (ILC1) and mucosal-associated invariant T cells can also curtail antitumour immune responses under certain inflammatory conditions191,223-227 Nonetheless, specific anti-inflammatory strategies for targeting these cell types are lacking, with the possible exception of CAFs. For instance, CXCR4 inhibition can render tumours responsive to immunotherapy by overcoming the fibrotic and immunosuppressive TME in both HCC and PDAC models228,229.

TNF can directly trigger activation-induced death of T cells, whereas TGFβ hampers cytotoxic immune cell function (FIG. 3g). Hence, targeting either of these cytokines using etanercept or alisertib, respectively, enhances the antitumour effects of ICIs108,116. Oncogenic pathways also impart unconventional inflammatory signals to directly suppress cytotoxic lymphocytes. For example, loss of the tumour suppressors APC in intestinal tumour cells or of PTEN in melanoma cells causes them to secrete Dickkopf-related protein 2 (DKK2), which impedes signal transducer and activator of transcription 5 (STAT5) activation within immune cells via binding to LDL receptor-related protein 5 (LRP5)230. Accordingly, an anti-DKK2 antibody reactivates tumour-infiltrating natural killer cells and CD8+ T cells and potentiates responses to PD-1 inhibition in mouse models of these cancers230.

Mitigating irAEs.

Anti-inflammatory agents also have indispensable roles in attenuating irAEs. As discussed, judicious use of an anti-IL-6R antibody can attenuate CAR T cell-induced CRS, which can otherwise limit the therapeutic value of this innovative immunotherapy231. IL-1R antagonism via anakinra or CAR T cell engineering is also capable of abrogating CRS-related mortality in mouse models231. Likewise, prophylactic use of TNF antagonists can ameliorate immune-related colitis associated with dual antiCTLA4 and anti-PD-1 inhibition in a mouse model of colon cancer108. Of importance, these anti-inflammatory therapies can further enhance immunotherapy efficacy and prolong survival in preclinical models, which are desirable characteristics for clinical use.

Pro-tumour perils of anti-inflammatories

Increasing clinical and preclinical evidence supports the broad therapeutic activity of metformin across a wide range of cancer types. However, BRAF-mutant melanoma has been demonstrated to escape the growth-inhibitory stress imposed by metformin232. The dual-specificity phosphatase DUSP6 negatively regulates ERK activity downstream of oncogenic BRAF, and AMPK hyperactivation by metformin results in the targeting of DUSP6 for degradation and thereby potentiates the ERK-driven expression of VEGFA, which bypasses the inhibitory effects of metformin and AMPK on mTORC1 signalling; thus, metformin counterproductively stimulates angiogenesis and accelerates tumour growth232. 

Inhibitors of mTOR (the kinase component of mTORC1) have long been considered as potential cancer treatments. As an immunosuppressive drug, however, the mTOR inhibitor rapamycin was found to activate the pro-tumorigenic factor STAT3 in a mouse model of steatotic HCC. Mechanistically, hepatocyte-specific loss of mTORC1 activity promoted hepatocarcinogenesis through the hyperactivation of AKT owing to the disruption of a negative feedback loop233. Another potential peril associated with metformin use relates to the consequent increases in circulating levels of growth/differentiation factor 15 (GDF15), which induces weight loss and correlates with cachexia and poor survival outcomes in patients with cancer234,235 .

With statin treatment for PDAC, the disruption of cholesterol biosynthesis can induce the sterol response element-binding protein (SREBP)-dependent expression of TGFβ and the epithelial-to-mesenchymal transition in cancer cells236, which might promote disease progression. Glucocorticoids are generally used as anti-inflammatory and immunosuppressive agents for treating chemotherapy-related or immunotherapy-induced adverse events in patients with advanced-stage cancer. Multi-omics data from patient-derived xenograft models indicate that these agents can activate glucocorticoid receptor signalling at distant metastatic sites, which in turn increases metastatic colonization and reduces mouse survival via upregulation of the tyrosine-protein kinase transmembrane receptor ROR1 (REF.237). The intravasation of tumour cells is a key process involved in metastatic dissemination to distant organs. Accordingly, the anticoagulant warfarin has been shown to increase vascular leakiness in mammary tumours, which was accompanied by substantial increases in the numbers of circulating tumour cells and lung metastases238.

Cytokine-specific or cytokine receptor-specific therapeutic agents have been tested in proof-of-concept trials across many cancer types; however, paradoxical findings underscore the importance of careful clinical application and further interrogation into their molecular mechanism. Despite the reported clinical benefits of anti-IL-1β therapy98, IL-1β is essential for cancer immunosurveillance in various contexts (FIG. 4). First, immunogenic cell death in established tumours is associated with the activation of DCs with intact inflammasome machinery to secrete IL-1β, which primes tumour-specific T cell responses239. Conversely, the anticancer effects of chemotherapeutic agents are dampened with the coadministration of an IL-1β-neutralizing antibody239. 

Second, the IL-1β-STAT1-interferon regulatory factor 1 (IRF1) axis is fundamental for IL-9 and IL-21 production by T helper 9 (TH9) cells, as demonstrated by the downregulation of Irf1, Il9 and Il21 expression in tumour-infiltrating TH9 cells following treatment with an IL-1R antagonist; this pathway was found to be crucial for the anticancer functions of TH9 cells in mice240. Third, in an Apc-based mouse model of CRC, IL-1R signalling in epithelial cells and T cells has pro-tumorigenic effects, whereas myeloid cell-specific IL-1R signalling counteracts tumour-promoting dysbiosis and inflammation241. Fourth, in mouse models of breast cancer, a systemic IL-1β-mediated inflammatory response has been shown to prevent metastasis-initiating cell differentiation and colonization of distant tissues, and the inhibition of IL-1R signalling at the primary tumour site results in metastatic progression242. 

In keeping with these preclinical findings, patients with breast cancer expressing high levels of IL-1β have been found to have better survival outcomes than those with low IL-1β expression242. Similarly, several different counterintuitive effects might explain the disappointing clinical outcomes achieved to date with agents targeting CSF1R. For example, in a GEMM of glioblastoma, macrophages that persist following CSF1R inhibition produce insulin-like growth factor 1 (IGF1), which can drive tumour recurrence through PI3K activation12. Surprisingly, CSF1R inhibition can also affect CAFs and, in particular, causes these cells to express the granulocyte-specific chemokine CXCL1, which initiates an immune inhibitory circuit243. 

Compelling evidence from single cell-based analyses of CRCs from mice indicates that antagonism of CSF1R depletes inflammatory F4/80hi myeloid cell populations while sparing those with pro-angiogenic and immunosuppressive properties13. In mouse models of breast cancer, treatment with a CCL2 antagonist reduces the abundance of TAMs and metastases by retaining inflammatory monocytes in the bone marrow, but the cessation of such treatment results in a lethal rebound effect mediated by IL-6 and VEGF secretion244 .

Conceivably, neutrophil-targeting strategies might also have poor anticancer efficacy because neutrophils have immunostimulatory activities in certain scenarios245,246. Likewise, the complement system might enhance the clinical responses to various cancer treatments, including monoclonal antibodies, vaccines and radiotherapy, reminiscent of the risks associated with complement-targeted therapeutics221,247. The depletion of CAFs might also induce immune evasion, for example, by increasing the abundance of regulatory T cells in the TME of PDAC248.

Antioxidants are believed to exert anticancer effects owing primarily to interference with pro-tumorigenic redox signalling. Paradoxically, in some preclinical models, antioxidant treatments accelerate tumour progression and metastasis through the inactivation of tumour suppressors or metabolic reprogramming249-252, mirroring outcomes observed in the clinical setting143.

Given the extensive molecular intersections and crosstalk, cellular adaptability, and organ-specific contexture, anti-inflammatory therapy targeting a single immunomodulatory factor might lead to tumour evolution or TME remodelling. Together, the paradoxical findings discussed above should prompt special caution when translating anti-inflammatory therapies into clinical use.

Conclusions

To date, many drugs and drug candidates have been used both preclinically and clinically to curtail the inflammatory conditions that fuel cancer development and progression. Numerous preclinical studies have provided insights into the mechanisms underlying the intricate interactions between cancer, inflammation and immunity, which should eventually lead to more innovative anti-inflammatory cancer therapies reaching the clinic. Considering the advances outlined herein, researchers and oncologists working together should be capable of developing successful strategies to inhibit cancer-related inflammation and of making such an approach a main-stay of modern cancer therapy. So far, anti-inflammatory strategies have proven rather effective in cancer prevention and conventional drugs such as aspirin have led to a much larger reduction in cancer mortality than novel and far more sophisticated targeted therapies. Given our improved understanding of the TME, research tools and animal models, we are hopeful that, in the next decade, several anti-inflammatory therapies will advance to the clinic and prove effective in preventing or treating cancer.

The numerous and diverse links between cancer and inflammation all present therapeutic opportunities, especially when the concept of ‘inflammation’ is broadened to include viral, bacterial and fungal infections. However, numerous hurdles and uncertainties remain in every step of translating an anti-inflammatory agent into clinical use. First, whether the inflammatory redundancies identified in preclinical models are targetable and druggable remains unclear. Second, the heterogeneity and plasticity of the TME present problems in targeting a single cytokine or even a single cell type. The effects of disrupted negative feedback loops and the activation of compensatory pathways are also hard to predict. Third, given that patients with cancer are typically assigned to conventional treatments, a need exists to identify more specific inflammatory targets that are responsible for therapy resistance or adverse events. 

Fourth, contrary to other targeted therapies, clinically applicable biomarkers for the selection of anti-inflammatory agents and assessment of their anticancer effects are lacking. Fifth, the effects of endogenous factors, such as the patient's age and microbiota, on the magnitude of inflammatory responses and the outcomes of anti-inflammatory treatments remain to be determined253,254. Notably, the composition of the microbiota has been shown to affect immunotherapy efficacy, suggesting that microbial interventions could potentially be leveraged to improve cancer prevention or treatment255,256. By necessity, defining a therapeutic paradigm for anti-inflammatory treatments would require optimized pharmaceutical programmes as well as appropriate animal models and clinical trial designs. In addition, integrative high-resolution analyses using multi-omics, single-cell and/or spatial-based technologies should provide deeper insights into local therapeutic responses and the exact cellular and molecular consequences of anti-inflammatory treatments. Finally, the deployment of personalized, multi-agent, anti-inflammatory regimens in the era of immunotherapy is possibly another key to treating cancer.

Supplementary Material

Refer to the Web version on PubMed Central for supplementary material.

Acknowledgements

The work of the authors is supported by grants from the National Key Research and Development Program of China (2016YFC0905900 to B.S.), the State Key Program of the National Natural Science Foundation (81930086 to B.S.; 81871970 and 81672801 to J.H.) and the US NIH (U01AA027681, R01CA211794, R01CA234128, P01CA128814, R01CA198103 and Tower Cancer Research Grant to M.K.). The work of J.H. is also supported by the Hundred Talent Program of Sun Yat-sen University. Figures in this review were drafted with the assistance of Dr Haiyan Zhang (Sun Yat-sen University Cancer Center).

References

1. Greten FR & Grivennikov SI Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019). [PubMed: 31315034] 

2. Grivennikov SI, Greten FR & Karin M Immunity, inflammation, and cancer. Cell 140, 883–899 (2010). [PubMed: 20303878] 

3. Balkwill F & Mantovani A Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001). [PubMed: 11229684] 

4. Diakos CI, Charles KA, McMillan DC & Clarke SJ Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 15, e493–e503 (2014). [PubMed: 25281468] 

5. Yang JD et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol 16, 589–604 (2019). [PubMed: 31439937] 

6. Brisson M et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries. Lancet 395, 575–590 (2020). [PubMed: 32007141] 

7. Bosetti C, Santucci C, Gallus S, Martinetti M & La Vecchia C Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019. Ann. Oncol 31, 558–568 (2020). [PubMed: 32272209] 

8. Chapelle N, Martel M, Toes-Zoutendijk E, Barkun AN & Bardou M Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population. Gut 69, 2244–2255 (2020). [PubMed: 32989022] 

9. Shi Y et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569, 131–135 (2019). [PubMed: 30996350] 

10. Calcinotto A et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 559, 363–369 (2018). [PubMed: 29950727] 

11. Ahern E, Smyth MJ, Dougall WC & Teng MWL Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy. Nat. Rev. Clin. Oncol 15, 676–693 (2018). [PubMed: 30232468] 

12. Quail DF et al. The tumour microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 (2016). [PubMed: 27199435] 

13. Zhang L et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442–459.e29 (2020). [PubMed: 32302573] 

14. Galon J & Bruni D Tumor immunology and tumour evolution: intertwined histories. Immunity 52, 55–81 (2020). [PubMed: 31940273] 

15. Shalapour S & Karin M Pas de deux: control of anti-tumour immunity by cancer-associated inflammation. Immunity 51, 15–26 (2019). [PubMed: 31315033] 

16. Hanahan D & Weinberg RA Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). [PubMed: 21376230]

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