Chronic inflammation within the tumor microenvironment (TME) is a critical driver of immune evasion, resistance to therapy, and progression of cancer, while epidemiological and immunological evidence indicates that allergic inflammation is also associated with the risk of several cancer types. Key pro-inflammatory cytokines: IL-6, IL-1 beta, TNF-alpha, and TGF-beta activate key signaling pathways such as STAT3, NF-kappa B, and HIF-1 alpha which create a self-amplifying cycle fostering angiogenesis, epithelial-mesenchymal transition, and immunosuppression. The accumulation of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages additionally promotes an immunologically "cold" TME limiting the efficacy of immune checkpoint blockade, chemotherapy, and radiotherapy. Recent advances have elucidated on how inflammatory signaling dynamically changes cellular and metabolic states fostering resistance. Targeting these inflammatory signaling axes has demonstrated promising therapeutic efficacy: IL-6R and IL-1 beta neutralization, JAK/STAT3 and NF-kappa B inhibition, TGF-beta blockade, and CXCR2 targeted strategies all have demonstrated the ability to restore anti-tumor immunity. Rationally designed combination therapies utilizing cytokine inhibition in combination with checkpoint blockades or anti-angiogenic agents are beginning to convert refractory tumors to responsive tumors. Herein we review mechanistic insights linking chronic inflammation to immunosuppression and treatment failure across multiple cancer types and discuss the translational promise of inflammation-targeted treatments. Targeting the TME through multi-variate inhibition of inflammatory pathways may be able to allow durable therapeutic responses to be achieved in tumors previously resistant to conventional and immune-based therapies.
[1]Beijing Univ Chinese Med, Wangqi Acad, Natl Inst TCM Constitut & Prevent Treatment Dis, Beijing 100029, Peoples R China.
[2]Jilin Univ, China Japan Union Hosp, Key Lab Pathobiol, Minist Educ,Nanomed & Translat Res Ctr, Changchun 130033, Peoples R China.
[3]Univ Chinese Med Longgang, Shenzhen Hosp Beijing, Shenzhen 518172, Peoples R China.
[4]Beijing Univ Chinese Med, Sch Tradit Chinese Med, Beijing 100029, Peoples R China.
[5]Southern Med Univ, Sch Tradit Chinese Med, Guangzhou 510515, Peoples R China.
[6]Inner Mongolia Med Univ, Hohhot 010110, Peoples R China.
[7]Hubei Univ Chinese Med, Hubei Shizhen Lab, Wuhan 430065, Peoples R China.
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