Targeting the tumor microenvironment for sensitization of colorectal cancer to chemotherapy and radiotherapy.

Colorectal cancer (CRC) is one of the world's leading causes of cancer-related death. Cancer cells within the tumor can expand through extensive interactions within the tumor microenvironment (TME). TME provides a dynamic niche that helps CRC cells resist attacks from the immune system or anticancer agents. Cancer-associated fibroblasts (CAFs), immune cells, vascular networks, and a remodeled extracellular matrix (ECM) can develop this microenvironment. These cells and networks interact in bidirectional communication with malignant cells. Cytokines, growth factors, and extracellular vesicles create paracrine loops that promote radio- and chemoresistance through activation of pro-survival signaling pathways. Moreover, metabolic crosstalk between stromal and cancer cells enhances survival and DNA repair capacity while suppressing apoptosis in malignant cells following exposure to chemoradiation. Hypoxia and increased ECM stiffness further limit drug penetration and amplify stemness in CRC, which further enhances radio- and chemoresistance. Recent studies highlight the central role of TME in radio- and chemoresistance of various malignancies, including CRC. This review focuses on these complex interactions and provides an overview of recent progress in preclinical and clinical studies aimed at improving chemo- and radiotherapeutic efficacy in CRC by targeting the TME.