Targeting inflammatory microenvironments: overcoming therapy resistance and immunosuppression

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-1β, TNF-α, and TGF-β activate key signaling pathways such as STAT3, NF-κB, and HIF-1α 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-1β neutralization, JAK/STAT3 and NF-κB inhibition, TGF-β 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.