Targeting Cancer-promoting Inflammation — Have Antiinflammatory Therapies Come Of Age? Part 1

Abstract

The immune system has crucial roles in cancer development and treatment. Whereas adaptive immunity can prevent or constrain cancer through immunosurveillance, innate immunity and inflammation often promote tumorigenesis and malignant progression of nascent cancer. The past decade has witnessed the translation of knowledge derived from preclinical studies of antitumour immunity into clinically effective, approved immunotherapies for cancer. 

By contrast, the successful implementation of treatments that target cancer-associated inflammation is still awaited. Anti-inflammatory agents have the potential to not only prevent or delay cancer onset but also to improve the efficacy of conventional therapeutics and next-generation immunotherapies. Herein, we review the current clinical advances and experimental findings supporting the utility of an anti-inflammatory approach to the treatment of solid malignancies. Gaining a better mechanistic understanding of the mode of action of anti-inflammatory agents and designing more effective treatment combinations would advance the clinical application of this therapeutic approach.

There is a close relationship between anti-inflammation and immunity. The main function of the immune system is to protect the body from foreign invading pathogens and damage substances. Anti-inflammation is a response method of the immune system. In the event of an infection or injury, the immune system releases a series of inflammatory factors that trigger an inflammatory response to deal with the pathogen or the damaging substance. This inflammatory response kills pathogens and removes damaging material, but it can also lead to inflammatory damage to tissues.

Normally, the immune system and inflammatory response subside on their own after the job is done. However, in some cases, the inflammatory response may be hyperactivated or chronic, leading to chronic inflammation and impaired immune function. Therefore, maintaining the normal function of the immune system and the balance of anti-inflammatory response is very important for human health. Some studies have shown that by maintaining a healthy lifestyle, including diet, exercise and good sleep, you can improve the function of the immune system and regulate the inflammatory response, thereby enhancing the body's ability to resist disease. Therefore, we must pay special attention to improving our immunity. Cistanche can enhance immunity, and the polysaccharides in the meat can regulate the immune response of the human immune system, improve the stress ability of immune cells, and enhance the bactericidal effect of immune cells.

Click cistanche tubulosa benefits

Inflammation is part of the innate immune response to danger signals, tissue disruption and/or infection. Transient and properly terminated inflammation is beneficial yet chronic inflammation increases cancer risk1. Numerous environmental factors, including carcinogenic microbes, pollutants, tissue-damaging radiation, tobacco smoke, diesel exhaust fumes, particulate matter and dietary factors, can evoke chronic inflammation in multiple organ systems, especially those that are exposed to the external environment. 

Left unresolved, chronic inflammatory responses can result in tumour promotion1. Tumour-associated inflammation, which entails intricate interactions between epithelial and stromal cells, can in some cases lead to epigenetic alterations that drive malignant progression and even initiate tumorigenesis. 

More generally, however, chronic inflammation results in the production of growth factors that support the development of newly emergent tumours and cause them to behave as “wounds that do not heal”2. Inflammation-reducing chemopreventive strategies that inhibit either the initiation or propagation of persistent inflammation might therefore prevent or delay cancer onset3. Anti-infective agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and other commonly used drugs capable of reducing inflammation, such as statins and metformin, have been reported to decrease cancer risk and incidence4-8.

Cancer cell-intrinsic or therapy-elicited mechanisms, including metabolic changes, cell stress and cell death, also constitute important sources of tumour-associated inflammation1. The continuous production of various cytokines, chemokines and growth factors within the tumour microenvironment (TME) supports cancer cell proliferation, evolution and survival as well as tumour vascularization and immune dysregulation, all of which contribute to tumour progression, invasion, metastasis and therapy resistance. Thus, the use of anti-inflammatory agents, either alone or in combination with cytotoxic agents and targeted therapies, is an appealing strategy for the treatment of inflammation-driven cancers. This approach is effective in various animal models9-11, although the complexity and plasticity of human cancers and their ecosystem present major hurdles that need to be overcome for anti-inflammatory therapy to become truly successful. 

For example, the inhibition of inflammation mostly slows down tumour growth rather than killing cancer cells and therefore needs to be combined with cancer-specific cytotoxic drugs to fully eradicate the tumours. In addition, owing to the depletion of general survival factors, anti-inflammatory drugs can inflict bystander effects on non-cancerous tissues, which can in turn result not only in TME remodelling and therapy resistance but also in the increased susceptibility of non-malignant cells to non-specific cytotoxicity that can lead to toxicities12,13.

The past decade has witnessed a burgeoning of effective treatments based on the activation of anti-tumour immune responses, for example, using immune-checkpoint inhibitors (ICIs) or genetically engineered T cells14. Such immunotherapies induce durable responses in a subset of patients; however, primary or acquired therapy resistance occurs in the vast majority of patients. 

In many cases, immunotherapy resistance is attributable to the presence of a pro-inflammatory and immunosuppressive TME15 (BOX 1). In this context, anti-inflammatory drugs that target immunosuppressive cells or cytokines might render the cancer more susceptible to immune-mediated rejection. Moreover, akin to the treatment of autoimmune diseases, selective targeting of the key drivers of immunotherapy-induced inflammation might increase the response-to-toxicity ratio and thereby improve therapeutic outcomes. Consequently, the combination of anti-inflammatory therapy with immunotherapy might evolve into a successful approach for circumventing the obstacles associated with current treatment modalities.

As a canonical cancer hallmark16, inflammation influences all stages of cancer development and treatment. The central inflammatory mediators governing cancer-autonomous intracellular modulation and intercellular communication within the TME have been covered in several reviews1,17-21. Herein, we draw on advances highlighting the use of anti-inflammatory agents for the prevention and/or treatment of solid malignancies, either in isolation or in combination with other therapeutic modalities. 

Rather than surveying all cancer-related inflammatory traits and mediators, we discuss what we believe are special opportunities and perils for anti-inflammatory approaches. Antiangiogenic agents and multi-kinase inhibitors, some of which exert anti-inflammatory effects, already occupy well-established places in the anticancer armamentarium and will not be included in this Review.

Anti-inflammatory treatments for cancer

Anti-infective agents

Several infectious diseases that result in chronic inflammation have been credibly linked to cancer initiation2. Accordingly, anti-infective agents have an important role in reducing the burden of inflammation-related cancers (FIG. 1).

Antiviral therapies.

Currently, hepatitis B virus (HBV) or hepatitis C virus (HCV) infections remain the leading causes of hepatocellular carcinoma (HCC)5. In addition to the direct oncogenic effects22, HBV or HCV infections can cause cancer-promoting inflammation. HBV vaccination has substantially reduced the global HCC burden and is continuing to do so; data from a population-based study indicate that the incidence of HCC in vaccinated birth cohorts is 75% lower than that in unvaccinated cohorts23. 

For infected individuals, interferon-based therapies, nucleoside or nucleotide analogues, and direct-acting antiviral agents, which inhibit the replication of HBV or HCV and/or promote their immune-mediated clearance, are estimated to decrease HCC risk by 50–80%5. Antiviral treatment is also effective in decreasing disease recurrence and improving postoperative survival outcomes in patients with HCC24-26. 

However, curative antiviral treatment of HBV or HCV infection alone is insufficient to entirely prevent HCC occurrence or recurrence, possibly owing to the presence of cirrhosis, diabetes, excess alcohol consumption, impaired liver function or other patient characteristics (such as age, sex, lifestyle and others)27-30.

Similarly, >90% of cervical cancers can be attributed to infection with human papillomavirus (HPV) types 16, 18, 31, 33, 45, 52 or 58 (REF.31). The results of international randomized controlled trials (RCTs) have demonstrated the substantial efficacy of HPV vaccines against cervical precancerous lesions (cervical intraepithelial neoplasia grade 2+). 

According to a large-scale meta-analysis reported in 2019 (REF.32), 5–9 years of population-based vaccination not only reduced the prevalence of HPV infection but also decreased the prevalence of cervical intraepithelial neoplasia grade 2+ by 51% in screened girls aged 15–19 years and by 31% in women aged 20–24 years. 

More recently, the results of a nationwide study in Sweden demonstrated that the cumulative incidence of cervical cancer was reduced from 94 cases per 100,000 in women who were unvaccinated to 47 cases per 100,000 in women vaccinated with the quadrivalent HPV vaccine (targeting HPV types 6, 11, 16 and 18) at 10–30 years of age33. Therefore, HPV vaccination has been implemented for cervical cancer prophylaxis in multiple age groups across different countries. High-level vaccination coverage in the population would likely result in cervical cancer elimination6, although specific antiviral drugs for treating established HPV infections are still lacking.

Epstein–Barr virus (EBV), the first tumour virus identified in humans, is associated with gastric cancer, nasopharyngeal cancer and lymphoma34. Currently, however, no approved therapies are available to prevent or treat EBV infection, despite intense research efforts.

Antibacterial therapies.

Helicobacter pylori, a bacteria that is carried by ~50% of the world population, is the strongest risk factor for gastric cancer and has therefore been designated by the WHO as a class I carcinogen35. Data from RCTs indicate that H. pylori eradication with broad-spectrum antibiotics not only prevents gastric cancer in individuals with asymptomatic infection or those without precancerous lesions but also lowers the rates of metachronous gastric cancer development in patients with early-stage gastric cancer or high-grade adenoma35-37. 

Among >2,250 residents of a high-risk region for gastric cancer in China, 2 weeks of H. pylori treatment resulted in early reductions in gastric cancer incidence and mortality that persisted beyond >22 years38.

Commensal bacteria, such as Fusobacterium nucleatum, have been found to increase the risk of colorectal cancer (CRC) development and to promote the progression of this disease39-42. Moreover, computational bioinformatics studies have identified microbial genetic signatures in blood or tumour tissues that distinguished patients with different cancer types from cancer-free individuals; these signatures provide a high-resolution landscape of cancer-associated microbes43. However, further studies are required to determine whether these bacteria induce cancer-promoting inflammation.

The antitumour effects of broad-spectrum antibiotics have been demonstrated in animal models, particularly in models of gastrointestinal cancers41,44,45; however, the current lack of species-specific antibiotics and the deleterious consequences of commensal dysbiosis have limited the therapeutic potential of microbial modulation in patients with cancer46. A future approach could entail the use of species-specific bacteriophages to selectively eliminate carcinogenic or tumour-promoting bacteria47. Vaccination against specific cancer-promoting microbes could also be considered, but antibacterial vaccines are rare and have mostly been ineffective.

Anti-fungal treatment.

Fungal infections are associated with oesophageal squamous cell carcinoma (ESCC) both in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, who have increased susceptibility to chronic fungal infections and in individuals without autoimmune disease48. These findings suggest that anti-fungal treatments could be used to reduce the incidence of ESCC; indeed, such therapy had anticancer effects in a mouse model of autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy-related ESCC48.

Nonsteroidal anti-inflammatory drugs

NSAIDs are widely used as antipyretics, analgesics or anti-platelet agents (platelet aggregation inhibitors) for cardiovascular disease (CVD) prophylaxis, operating through the inhibition of cyclooxygenase (COX) activity. One such NSAID, aspirin, has been identified as a broad-spectrum cancer-preventive agent based on data from clinical and epidemiological studies24 (FIG. 1). Since 2015, the US Preventive Services Task Force has recommended the routine use of aspirin for the prevention of CRC among individuals aged 50–59 years who have a high risk of CVD and a low risk of bleeding49. A systematic review and meta-analysis of observational studies on aspirin use and digestive-tract cancers published up to March 2019 revealed that regular users had a 27% lower CRC risk (across 45 studies), a 33% lower ESCC risk (13 studies), a 39% lower risk of adenocarcinoma of the oesophagus and gastric cardia (10 studies), a 36% lower risk of stomach cancer (14 studies), a 38% lower risk of hepatobiliary cancer (5 studies) and a 22% lower risk of pancreatic cancer (15 studies) than non-users7. 

However, in other large-cohort prospective studies, regular aspirin use was not associated with a statistically significant reduction in pancreatic cancer risk, except in individuals with diabetes or higher baseline levels of systemic inflammation50. Nevertheless, the anti-inflammatory properties of aspirin make it a viable chemopreventive for those with an elevated risk of inflammation-related cancer. In two nationwide observational cohort studies of patients with chronic viral hepatitis in Sweden or Taiwan51,52, the long-term use of low-dose aspirin (≤160 or ≤100 mg daily, respectively, for ≥90 days) reduced the risk of HCC by 31% and 29%, respectively, without increasing the risk of gastrointestinal bleeding. Aspirin also seems to benefit patients with a hereditary cancer risk: in a double-blind RCT, patients with Lynch syndrome who were assigned to aspirin treatment had a 37% lower risk of developing CRC compared with those who received a placebo53. 

An analysis of data from two large-cohort prospective observational studies performed in the USA revealed that regular aspirin use for at least 6 years decreased the overall incidence of gastrointestinal-tract cancers by 15% and of CRC by 19% but had no effect on breast, prostate or lung cancer incidence54. Furthermore, pooled results from RCTs in the setting of CVD prophylaxis (8 eligible trials encompassing 25,570 patients and 674 cancer deaths) demonstrated that daily aspirin use mitigated distant metastasis and deaths from certain cancers, specifically adenocarcinomas (particularly those that were non-metastatic at diagnosis)55.

Importantly, the post-diagnosis administration of aspirin is sufficient to reduce overall gastrointestinal or oesophageal cancer mortality56. The survival benefit from post-diagnosis aspirin use specifically in patients with CRC was greater among those with PIK3CA-mutant and COX2-positive tumours57 or among those with low tumoural levels of PD-L1 (REF.58). The ongoing Add-Aspirin trial (ISRCTN74358648) is evaluating the effect of aspirin use after primary radical therapy for gastroesophageal, colorectal, breast or prostate cancer on disease recurrence and survival outcomes, with a predefined feasibility analysis revealing that this adjuvant therapy approach is well tolerated with a low incidence of toxicities (0.5% grade 3 and no upper gastrointestinal bleeding of any grade)59. However, a cautionary note comes from the ASPREE study; in this placebo-controlled RCT, low-dose aspirin (100 mg daily) was associated with increases in bleeding risk, in the incidence of cancers diagnosed with metastasis and, correspondingly, in cancer mortality in older adults (>65 years of age) without CVD, dementia or physical disability60-62

Celecoxib and rofecoxib, two selective COX2 inhibitors, have demonstrated efficacy in the prophylaxis of colorectal adenomas (or adenomatous polyps) but are not routinely recommended for such indications because of their serious CVD risks63-65. A randomized phase II trial revealed that the addition of celecoxib to chemoradiotherapy did not provide an overall survival (OS) or progression-free survival (PFS) benefit in patients with unresectable stage III non-small-cell lung cancer66. In a trial involving patients with CRC, preoperative treatment with celecoxib did not improve responses to neoadjuvant immunotherapy with anti-PD-1 plus anti-CTLA4 antibodies67, although results of a preclinical study indicate that the inhibition of prostaglandin E2 (PGE2) synthesis (for example, through genetic ablation of COX expression) can overcome immune evasion in some mouse models of cancer68.

Of therapeutic significance, the intraoperative administration of ketorolac, an inhibitor of both COX1 and COX2, reduced the frequency of distant disease recurrence in patients with breast cancer, particularly in those with an elevated BMI (≥25 kg/m2 ) 69. The use of other non-aspirin NSAIDs, such as ibuprofen, has also been associated with a decreased CRC risk, but further investigation of their overall therapeutic value in the prevention and/or treatment of cancer is warranted70.

Lipid-lowering drugs

High serum levels of LDL, a protein complex that is loaded with cholesterol, can lead to harmful inflammation. Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that block cholesterol biosynthesis and are prophylactically used to treat CVD. Statins also have poorly understood anti-inflammatory properties, which are important for their protective activity against CVD and have not been reported for other cholesterol-lowering treatments71. Early observations of the association between statin use and CRC risk came from RCTs in the setting of CVD71. In the population-based case–control Molecular Epidemiology of CRC study72, self-reported statin use for at least 5 years was significantly associated with a lower CRC risk (OR 0.50, 95% CI 0.40–0.63), even after adjustment for the presence or absence of hypercholesterolaemia as well as NSAID use, among other factors (OR 0.53,95% CI 0.38–0.74). A retrospective cohort study has revealed that prior statin use might reduce post-colonoscopy CRC incidence 73. However, the results of meta-analyses of RCTs and other cohort studies indicate only modest protective effects of statins on CRC74-76.

In a cohort of 7,657 patients with newly diagnosed CRC, post-diagnosis statin use was associated with decreased cancer-specific mortality (fully adjusted HR 0.71, 95% CI 0.61–0.84)77. Nonetheless, when additional confounding variables were considered, neither population-based cohort studies nor the Surveillance, Epidemiology, and End Results (SEER)–Medicare database provided evidence supporting improved cancer-specific survival among statin users78,79.

Similar to other approaches to HCC chemoprevention, a profound beneficial effect of statin use has been observed in patients with viral hepatitis, diabetes or liver cirrhosis yet lower or no statistically significant effects have been observed in the general population80-87. Of note, the statin-related benefits were greater in Asian populations than in Western populations. Observational studies and clinical trials have also revealed that statins might be protective against H. pylori-related gastric cancer in both Asian and Western populations88. Well-designed, prospective, multicentre studies are needed to further validate the chemopreventive activity of statins.

Metformin

Type 2 diabetes mellitus (T2DM) has been linked to an increased incidence of and mortality from many types of cancers, including colorectal, pancreatic, hepatobiliary, breast and endometrial cancers89. Metformin is an oral biguanide used for the first-line treatment of T2DM. Data from epidemiological studies and meta-analyses have demonstrated an association between metformin use and a reduced incidence of pancreatic, hepatocellular, lung, colorectal and breast cancers in patients with T2DM89. Of note, a systematic review encompassing 10 studies involving a total of 334,307 patients with T2DM revealed that metformin use was associated with a 50% lower risk of HCC90-92. Specifically, this association was seen in a meta-analysis of observational studies (n = 8) after adjusting for potential confounding factors, such as the use of other antidiabetic agents; however, the evidence is still insufficiently strong to recommend chemoprevention using metformin in patients at high risk of HCC90-92. Therefore, additional prospective trials or observational studies evaluating the ability of metformin to reduce HCC risk are needed.

The results of a multicentre, double-blind, placebo-controlled phase III trial involving 151 patients without diabetes who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy support a potential role for metformin in CRC prevention93. In this group, treatment with low-dose metformin (250 mg per day) resulted in a significantly lower incidence of metachronous polyps (RR 0.67, 95% CI 0.47–0.97) or adenomas (RR 0.60, 95% CI 0.40–0.92)93.

Given its low cost and good safety profile (the most serious complication is lactic acidosis, with an incidence of about 3–10 cases per 100,000 person-years)94, metformin has been extensively investigated as a possible therapeutic and chemopreventive agent in different cancer settings95 (FIG. 1). The anticancer activity of metformin is being evaluated in numerous ongoing phase II and III trials (Supplementary Table 1). 

For example, the combinational use of metformin and low-dose aspirin is being investigated for tertiary prevention (to avoid disease recurrence) after the resection of stage I–III CRC (NCT03047837) 96. Encouragingly, in an open-label, phase II study involving patients with advanced-stage EGFR-mutant non-small-cell lung cancer97, the addition of metformin to EGFR tyrosine kinase inhibitor therapy significantly prolonged PFS (median 13.1 months versus 9.9 months with EGFR tyrosine-kinase inhibitors alone; P = 0.03) and OS (median 31.7 months versus 17.5 months, respectively; P=0.02).

Targeted anti-inflammatory agents

IL-1 antagonists.

In the double-blind, placebo-controlled phase III CANTOS trial that had the primary aim of investigating the efficacy of the anti-IL-1β antibody canakinumab in preventing recurrent CVD, this anti-inflammatory therapy was found to have unanticipated activity in preventing lung cancer98. The CANTOS study included 10,061 patients who had atherosclerosis, a previous myocardial infarction and high serum levels of high-sensitivity C-reactive protein (CRP; ≥2 mg/l) but were free of previously diagnosed cancer. Of note, canakinumab therapy led to a dose-dependent reduction in circulating CRP and IL-6 levels. At a median follow-up duration of 3.7 years, canakinumab (300 mg subcutaneously every 3 months) was associated with a 67% reduction in lung cancer incidence (P < 0.0001), with a 39% reduction also seen with 150 mg dosing (P=0.034), as well as with a 77% reduction in lung cancer mortality (P = 0.0002), compared with placebo. However, fatal infections or sepsis occurred more frequently with canakinumab than with a placebo, warranting caution. Further trials specifically designed to evaluate the efficacy of canakinumab in cancer prevention and treatment are ongoing (Supplementary Table 1).

The first-in-class anti-IL-1α monoclonal antibody MABp1 was developed to target systemic inflammation in cancer. Data from phase I–III trials demonstrate that MABp1 is well tolerated, with no dose-limiting toxicities observed, and can result in the stabilization of disease and symptoms (lean body mass and/or pain, fatigue or anorexia) in patients with various treatment-refractory advanced-stage solid tumours99,100. The investigators of the phase III trial of this agent99,100, which specifically involved patients with CRC refractory to oxaliplatin and irinotecan, concluded that MABp1 constitutes a new standard in the management of advanced-stage CRC.

Blockade of the TNF pathway.

Monoclonal antibody-based agents targeting TNF (infliximab) or its receptor (etanercept) have also been tested for tolerability and biological activity in patients with advanced-stage cancers; the observed therapeutic effects were modest, although the blockade of TNF signalling might contribute to disease stabilization101-105. ICIs are commonly associated with immune-related adverse events (irAEs) such as moderate-to-severe colitis106. Infliximab has been recommended for the management of irAEs that are refractory to glucocorticoids107. Furthermore, the treatment of advance-stage melanoma with either infliximab or certolizumab (another monoclonal antibody-based anti-TNF drug), each administered concomitantly with the anti-CTLA4 antibody ipilimumab and the anti-PD-1 antibody nivolumab, is currently being evaluated in a phase Ib trial (NCT03293784). Notably, anti-TNF therapy might not be feasible in patients with hepatitis given the indispensable role of TNF–TNFR1 signalling in liver regeneration108 .

Anti-IL-6 agents.

IL-6 is one of the most crucial cytokines bridging cancer-promoting inflammation and immunosuppression109. Anti-IL-6 drugs, which are routinely used in the treatment of autoimmune conditions, have been tested in anticancer applications. In several phases, I–II clinical trials, however, the clinical response to the anti-IL-6R antibody tocilizumab or the anti-IL-6 antibodies canakinumab and siltuximab has been poor in patients with prostate, lung or breast cancers, multiple myeloma, or cancer-related cachexia (reviewed previously109,110). Thus, monotherapy with agents targeting IL-6 might have limited activity against solid tumours in non-stratified patients, although anti-IL-6 therapy is effective in reversing irAEs caused by immunotherapy111. In particular, tocilizumab has been approved for the treatment of cytokine-release syndrome (CRS) associated with chimeric antigen receptor (CAR) T cell therapy112.

Inhibition of TGFβ signalling.

Transforming growth factor-β (TGFβ)-targeted therapies have also been considered for the management of cancer. Galunisertib, a small molecule inhibitor of the TGFβR1 kinase, has been demonstrated to be safe in patients with various cancers113. When administered in combination with gemcitabine to patients with unresectable pancreatic ductal adenocarcinoma (PDAC) or with sorafenib to patients with advanced-stage HCC, alisertib had modest therapeutic activity114,115. Pending the outcome of trials using alisertib, more potent and more specific small-molecule inhibitors of TGFβR1 have been developed and are being tested in combination with chemotherapy or emerging immunotherapy modalities (Supplementary Table 1). In addition, isoform-specific anti-TGFβ, pan-TGFβ or bi-functional anti-PD-L1-TGFβR2 antibodies are all being tested in phase I trials of different anticancer indications116 .

Targeting cytokines mediating TAMs and MDSCs.

Antibodies or other antagonists targeting the colony-stimulating factor 1 receptor (CSF1R), the CC-chemokine receptor 2 (CCR2) or CCR5, which can deplete tumour-associated macrophages (TAMs) or otherwise abrogate their immunosuppressive inflammatory activities, are safe and tolerable in phase I trials117-120. Although anti-CSF1R antibodies did not have robust anticancer activity either alone or in combination with chemotherapy117,118, CCR2 (REF.119) and CCR5 (REF.120) antagonism led to objective clinical responses in patients with advanced-stage PDAC or CRC, respectively. Owing to their immunomodulatory potential, these TAM-targeted agents are also being explored for potential synergy with ICIs121.

The CXC-chemokine receptor 1 (CXCR1) and CXCR2 antagonist SX-682, which was designed to disrupt the trafficking of myeloid-derived suppressor cells (MDSCs) to tumours, is being tested in combination with pembrolizumab (an anti-PD-1 antibody) in phase I/II trial involving patients with metastatic melanoma (NCT03161431). Additionally, data from the COMBAT trial (NCT02826486) indicate that the CXCR4 antagonist BL-8040 depletes MDSCs and increases the tumour infiltration of CD8+ T cells, with evidence also indicating that this agent might cooperate with pembrolizumab to improve antitumour immune responses and chemotherapy efficacy in patients with PDAC122.

Natural anti-inflammatory supplements

In addition to the drugs discussed above, some natural compounds might also help control inflammation and cancer. As an antioxidant and anti-inflammatory dietary supplement, vitamin C has been extensively explored for potential anticancer effects. However, contemporary data indicate that pharmacological vitamin C can enhance the cytotoxicity and therapeutic sensitivity of cancer cells only when administered intravenously at high doses and that it exerts anticancer effects primarily via pro-oxidant, rather than antioxidant, activity123.

Vitamin D can regulate the host immune system to potentiate immune responses as well as to attenuate harmful inflammatory reactions124. The results of several prospective observational studies indicate that plasma levels of the major circulating form of vitamin D, 25-hydroxyvitamin D, are inversely associated with the risk of CRC and prostate cancer125-127. Pre-treatment vitamin D levels have also been associated with PFS and OS in patients with advanced-stage CRC or Hodgkin lymphoma who received first-line chemotherapy128,129. However, the prophylactic benefit of vitamin D supplementation remains questionable. 

In 2,303 randomized postmenopausal women without a prior cancer diagnosis, nutritional supplementation with vitamin D and calcium did not reduce the risk of all-type cancer at 4 years compared with placebo130. In the VITAL (Vitamin D and Omega-3) trial, which involved a total of 25,871 cancer-free men and women (aged >50 years and >55 years, respectively), vitamin D supplementation (2,000 IU per day) for a median of 5.3 years was not associated with a reduced incidence of invasive cancer compared with placebo131. 

The findings of a meta-analysis of 52 RCTs involving 75,454 participants suggest that vitamin D supplementation could reduce the risk of cancer-related death by 16%132. Nonetheless, in the double-blind, phase II SUNSHINE trial involving patients with advanced-stage CRC, the addition of high-dose (8,000 IU per day for 14 days, followed by 4,000 IU per day) versus standard-dose (400 IU per day) vitamin D to standard chemotherapy resulted in no statistically significant difference in PFS (although a statistically significant difference in PFS was observed on the multivariate analysis)133. Likewise, in the randomized single-centre AMATERASU trial in patients with digestive tract cancers, postoperative vitamin D supplementation did not result in improved 5-year relapse-free survival or OS as compared with placebo134. In keeping with the anti-inflammatory properties of vitamin D, intake of this vitamin has been correlated with a reduced risk of ICI-related colitis135 .

The administration of long-chain omega-3 fatty acids, an anti-inflammatory nutritional supplement that is often tested in parallel with vitamin D, is not effective in cancer prevention136,137. However, omega-3 supplementation has been associated with a reduced risk of colorectal adenomas among individuals with low plasma levels of such fatty acids at baseline and in the African-American population (OR 0.59, 95% CI 0.35– 1.00)137. Similarly, the seAFOod Polyp Prevention trial did not meet its primary endpoint (an improved adenoma detection rate) but did suggest that the omega-3 polyunsaturated fatty acid eicosapentaenoic acid has a chemopreventive effect in reducing recurrent adenoma multiplicity138. Of note, contradictory results have been obtained in trials investigating other dietary supplements, including β-carotene, α-tocopherol (vitamin E), selenium, vitamin B12 and folic acid, some of which were even associated with an increased cancer risk or diminished chemotherapy responses38,137,139-143.

The antimicrobial, anti-platelet and lipid-lowering effects attributed to garlic supplements have earned these supplements a place in cancer prevention strategies. In an RCT conducted in a high-risk region for gastric cancer in Shandong, China, 3,365 participants were assigned to three different interventions (H. pylori treatment; vitamin C, vitamin E and selenium supplementation; or garlic extract and oil supplementation) or appropriate placebos; among these individuals, the use of garlic supplements for >7 years did not decrease the incidence of gastric cancer but did significantly reduce mortality from this disease (HR 0.66, 95% CI 0.43–1.00)38.

As a plant-derived natural alkaloid with antioxidant and antimicrobial properties, berberine might have a wide range of therapeutic benefits for patients with digestive systems or metabolic diseases. In a double-blind, placebo-controlled RCT, berberine at 0.3 g twice daily significantly decreased the recurrence rate of colorectal adenoma and polypoid lesions after polypectomy (RR 0.77, 95% CI 0.66–0.91; P=0.001)144. Given the rather short follow-up duration of this study (2 years), the ability of Berberine to prevent the occurrence of advanced colorectal adenomas or CRC remains to be determined.

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