Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although substantial advances in chemotherapy, molecular targeted therapy, and immunotherapy have improved clinical outcomes in select patient populations, therapeutic resistance remains the major obstacle to durable disease control. Accumulating evidence suggests that drug resistance in CRC does not result from isolated molecular events, but rather reflects a dynamic and adaptive process driven by coordinated tumor intrinsic programs, as well as continuous interactions between tumor cells and their surrounding microenvironment. In this Review, we present a systematic overview of the clinical manifestations and biological foundations of resistance to cytotoxic chemotherapy, targeted therapy, and immune checkpoint blockade in CRC. We summarize tumor intrinsic resistance mechanisms, including oncogenic signaling reprogramming, DNA damage response modulation, metabolic and redox adaptation, ubiquitin-regulated proteostasis, epigenetic and RNA-mediated regulation, evasion of programmed cell death, and the emergence of cancer stem cell and drug-tolerant persister states. In parallel, we examine the contribution of the tumor microenvironment, including cancer-associated fibroblasts, immunosuppressive immune networks, extracellular vesicle-mediated communication, and the gut microbiota, in establishing protective niches that promote resistance and limit therapeutic efficacy. We further discuss how emerging approaches such as single-cell and spatial multi-omics profiling, liquid biopsy, and longitudinal molecular monitoring have reshaped the understanding of drug resistance as a continuous evolutionary process under therapeutic selection pressure. Finally, we highlight therapeutic strategies inspired by systems biology and evolutionary principles, with an emphasis on rational combination and sequencing regimens, targeting adaptive vulnerabilities, and remodeling the tumor ecosystem to enable more durable and precise control of CRC.