FIGURE 3.

Cancer-associated fibroblast (CAF) immunomodulatory mechanisms. CAFs-derived secretome primarily alters the immune microenvironment around the stroma by infusing immunosuppression. Inhibition of NK cells, generation of T_reg cells, and M2 polarization of macrophages are the key reasons behind the immunosuppression. Besides, CAFs can block antigen presentation by inhibiting DCs, largely impeding cell-mediated immunity. In addition, CAF-secretome is responsible for N1 to N2 conversion, thereby minimizing the T-cell (CD8⁺)-mediated cytotoxicity against tumor cells. Moreover, CAFs are known to regress the impact of cancer immunotherapy and favor tumor progression via the reduction of T_H1 cells through their conversion into T_H2 cells and generation of T_H17 cells, respectively (Dikov et al., 2005; Kitamura et al., 2005; Flavell et al., 2010; Allard et al., 2016; Hashimoto et al., 2016; Kitamura et al., 2017; Mantovani et al., 2017; Takahashi et al., 2017; Cheng et al., 2018; Nakamura et al., 2018; Qian et al., 2018; Liu et al., 2019a; Monteran and Erez, 2019a; Masucci et al., 2019; Owusu-Ansah et al., 2019; Zhang et al., 2019; An et al., 2020; Veglia et al., 2021).