Fig. 6

Crosstalk in neuron-immune-tumor microenvironment for cancer cell fate determination. The evolving tumor microenvironment is essential during all stages of cancer progression, supported by multiple key representative elements, including multiple immune cells (T-cell, Treg, NK cell, TAMs, neutrophil, and monocyte), CAFs, neurons, ECM, and cytokines. Normally, cancer cells are attacked to destruction by the immune system at the earliest stages of tumor initiation, while the immune system is gradually influenced along with the development of cancer to eventually provide pro-cancer functions. The hypoxic environment in which the cancer grows promotes immune cells and CAFs to secrete VEGF, IL-10, TGFβ, MMP-9, and integrin to support tumor growth, proliferation, angiogenesis, dormancy, EMT, invasion and metastasis. Meanwhile, neurons in tumor microenvironment are recruited to promote tumor malignant development, in turn, cancer cells secrete factors and EVs to regulate axongenesis, neuron reprogramming, and neurogenesis. (The arrows represent induct, and the horizontal lines represent inhibit)