Immunocytes interact directly with cancer cells in the tumor microenvironment: one coin with two sides and future perspectives

Abstract

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.

Keywords: cancer cells; direct and dual effect; immunocytes; solid tumor; tumor microenvironment.

Figure 1

The direct antitumor action of immune cells and the counteraction of tumor cells. Through the Fas/Fasl pathway, ADDC pathway, and TRAIL pathway, immune cells exert direct cytotoxic effects on tumor cells. Simultaneously, they can release granule enzymes, IFN-γ, TNF-α, ROS, INOS, and other mediators to generate cytotoxicity. In addition, Th9 cells induce apoptosis in tumor cells by releasing IL-9. It is noteworthy that tumor cells, in turn, enhance the cytotoxicity of NK cells and CTL cells through secretion lactic acid, TGF-β, PGE2, and VEGF-A.

Figure 2

The direct tumor-promoting action of immune cells and the counteraction of tumor cells. Through the secretion of multiple chemokines, cytokines and other effector molecules such as IL-4, interleukin-5, and so on, immunocytes promote tumor cells through the following ways: promoting the proliferation of tumor cells, promoting the migration and metastasis of tumor cells and promoting tumor angiogenesis. It is worth noting that tumor cells can in turn promote the activation and recruitment of macrophages and Th2 cells via secreting CCLX, IL-33, IL-4, IL-10, and M-CSF, thus promoting the formation of loops.