Metabolic reprogramming of myeloid‑derived suppressor cells in colorectal cancer: Mechanistic insights and immunometabolic targeted rehabilitation (Review)

Metabolic reprogramming of myeloid-derived suppressor cells (MDSCs) plays a role in immunotherapy resistance in colorectal cancer (CRC).This metabolic reprogramming appears to be coordinated by oncogenic mutations (such as adenomatous polyposis coli, KRAS and TP53) through a proposed self-reinforcing 'mutation-metabolism-suppression' axis.In the present review, four core metabolic pillars sustaining MDSC pathogenicity and the epimetabolic regulation that durably locks them into a suppressive state were examined.Furthermore, two emerging dimensions were highlighted: The spatial metabolic antagonism through which MDSCs may construct a metabolically hostile zone to limit the functional activity of tertiary lymphoid structures, and the remote manipulation of MDSC function by gut and intratumoral microbiota-derived metabolites.To transcend the limitations of non-specific myeloid depletion, immunometabolic rehabilitation is proposed as a potentially transformative framework targeting intrinsic metabolic vulnerabilities to functionally reprogram MDSCs from an immunosuppressive to a homeostatic or immunostimulatory phenotype.By integrating emerging spatial omics for precise target validation, artificial intelligence-guided rational drug design and microbiome modulation, this paradigm provides a strategic roadmap for next-generation precision immunotherapy, aiming to achieve durable responses across both microsatellite stable and microsatellite instability-high CRC.