Therapeutic resistance remains a major barrier to effective treatment in colorectal cancer (CRC), where the tumor microenvironment (TME) plays a pivotal role in modulating responses to chemotherapy, immunotherapy, and targeted therapies. This review synthesizes current evidence on how cellular and non-cellular TME components contribute to resistance mechanisms in CRC. Key immune cells, including T cells, macrophages, neutrophils, natural killer cells, dendritic cells, and myeloid-derived suppressor cells, orchestrate immunosuppressive networks that impair drug efficacy. For instance, regulatory T cells and M2-polarized macrophages promote chemoresistance via cytokine secretion and metabolic reprogramming, while neutrophils and myeloid-derived suppressor cells hinder immune checkpoint blockade through extracellular trap formation and T-cell exhaustion. Non-cellular elements, such as extracellular matrix remodeling, hypoxia-induced metabolic shifts, and dysregulated cytokines like IL-6 and TGF-β, further exacerbate resistance by fostering epithelial-mesenchymal transition and angiogenesis. Tables highlight specific molecular axes and therapeutic implications. By elucidating these interactions, this article underscores the potential of TME-targeted strategies, such as macrophage reprogramming, cytokine inhibition, and combination therapies, to overcome resistance and improve clinical outcomes in CRC patients. Future research should prioritize integrating TME biomarkers for personalized treatment approaches.
Han et al. (2026) studied this question.