Deciphering the colorectal tumor microenvironment: Interactions and targets for effective therapy

The colorectal tumor microenvironment (TME) includes a stroma that exerts diverse effects on cancer cells that can either promote metastasis and resistance to anticancer agents or suppress tumor growth. Recent studies suggest that a comprehensive elucidation of the intricate cellular and molecular interdependencies within this ecosystem is crucial for developing effective anticancer therapeutic strategies. This milieu includes various types of cells, such as malignant cells with diverse differentiation states, stromal components such as cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), and diverse immune cells, which mainly suppress cytotoxic CD8⁺ T lymphocytes (CTLs). However, other immune and stromal cells can enhance antigen presentation and CTL activation. Dynamic interactions and communications among different cells are mediated by soluble mediators, such as cytokines, exosomes, and chemokines, which control the recruitment of immune cells. Accumulated cells can enhance cancer stemness, invasion, and the evolution of new mechanisms for resistance to different anticancer drugs or radiotherapy. This review provides the current understanding of these complex interactions to delineate novel therapeutic targets and strategies, such as combination modalities, for providing an effective therapy.