Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment

Abstract

Immunotherapy is a currently popular treatment strategy for cancer patients. Although recent developments in cancer immunotherapy have had significant clinical impact, only a subset of patients exhibits clinical response. Therefore, understanding the molecular mechanisms of immunotherapy resistance is necessary. The mechanisms of immune escape appear to consist of two distinct tumor characteristics: a decrease in effective immunocyte infiltration and function and the accumulation of immunosuppressive cells in the tumor microenvironment. Several host-derived factors may also contribute to immune escape. Moreover, inter-patient heterogeneity predominantly results from differences in somatic mutations between cancers, which has led to the hypothesis that differential activation of specific tumor-intrinsic pathways may explain the phenomenon of immune exclusion in a subset of cancers. Increasing evidence has also shown that tumor-intrinsic signaling plays a key role in regulating the immunosuppressive tumor microenvironment and tumor immune escape. Therefore, understanding the mechanisms underlying immune avoidance mediated by tumor-intrinsic signaling may help identify new therapeutic targets for expanding the efficacy of cancer immunotherapies.

Keywords: Immune escape; Immunosuppressive cells; Immunosuppressive tumor microenvironment; T cell infiltration; Tumor-intrinsic signaling.

Fig. 1

Tumor-intrinsic signaling induces the exclusion and dysfunction of effective immunocytes. Oncogenic drivers of tumors, including β-catenin, STAT3, PI3K/PTEN/AKT/mTOR, p53, NF-κB, and RAS/RAF/MAPK signaling, are activated in the tumor microenvironment. These oncogenic signaling pathways not only downregulate the production of chemokines, which further decrease the recruitment of DCs, macrophages, T cells, and NK cells to tumor sites, but also induce immunosuppression of these immunocytes. In addition, tumor-intrinsic signaling can induce PD-L1 expression in tumor cells, leading to T cell dysfunction in the tumor microenvironment

Fig. 2

Tumor-intrinsic signaling mediates the recruitment and differentiation of immunosuppressive cells. Oncogenic pathways in tumor cells can be activated to promote the production of several chemokines and cytokines, which further enhance the recruitment and polarization of immunosuppressive cells, such as TAMs, MDSCs, Tregs, and TANs, to tumor sites. These immunosuppressive cells within the tumor microenvironment may also contribute to immunoresistance in cancers

Fig. 3

Tumor-intrinsic signaling as a therapeutic target for cancers. The activation of tumor-intrinsic signaling regulates and promotes the immunosuppressive tumor microenvironment, which includes exclusion and dysfunction of effective immunocytes and recruitment and differentiation of immunosuppressive cells. Therefore, targeting the tumor-intrinsic signaling is a potential strategy for cancer treatment