Infiltration of TAMs and autophagy
High infiltration of TAM usually has a poor prognosis in most human tumor diseases[55]. It has been shown that the infiltration of immune cells into tumors is orchestrated by cytokines and chemokines released from the tumor microenvironment acting in autocrine and/or paracrine manner(s), thus facilitating the communication between several types of cells within the TME in order to control and shape tumor growth[56]. Among them, TAMs, as the main tumor-infiltrating immune cell population, are usually induced as ”accomplices” by tumor cells to promote tumor immune escape, angiogenesis, tumor growth and metastasis[57]. It was demonstrated that inhibition of tumor-associated macrophages-induced autophagy in hepatocellular carcinoma enhances the cytotoxicity of the chemotherapeutic agent oxaliplatin against hepatocellular carcinoma cells[58]. F. nucleatum was found to be a major oncogenic bacterium that drives TAMs formation and induces infiltration. The main mechanisms are manifested in, F. nucleatumwas able to bind to membrane proteins on the surface of OSCC cells to activate autophagy, leading to GLUT1 aggregation in the plasma membrane and extracellular lactate deposition, thereby increasing extracellular acidification and M2-like TAM formation. Inhibition of both autophagy signaling and GLUT1 can effectively reduce the formation of TAMs and inhibit the progression of OSCC cells[49, 59]. This provides a theoretical basis to further investigate the complex relationship between TAM infiltration, autophagogenesis, and tumor cell development. Notably, one study found that high M1 macrophage infiltration correlated with better treatment profiles in cancer patients. Increased secretion of the pro-inflammatory factors CCL5 and CXCL10 in TME of melanoma and CRC tumor cells when induced with the autophagy inhibitor VPS34 inhibitor (SB02024 or SAR405), which in turn promoted major immune effector cells (NK cells, CD8+T and CD4+T cells, DC cells and M1 macrophages) infiltration increased, and thus reversed resistance to anti-PD-1/PD-L1 therapy in melanoma and colorectal cancer tumor models[60]. In summary, these studies suggest that autophagy exerts a pro- or oncogenic effect on the accumulation of TAMs in TME, but the interaction between autophagy and the infiltration of such cytotoxic effector immune cells is largely understudied.