Molecular mechanisms of colorectal cancer: from carcinogenesis and molecular classification to targeted therapy

Abstract Colorectal cancer (CRC) is a heterogeneous disease that results from the progressive accumulation and interactions at multiple levels of genetic alterations, which lead to the transformation of normal colonic epithelium into malignant colorectal tumors. Understanding the molecular basis of CRC pathogenesis, together with the interactions between genetic alterations, epigenetic modifications, environmental and lifestyle factors, is essential for improving prevention, diagnosis, prognosis, and treatment strategies. This review aims to provide a critical reference point for understanding the temporal dynamics of colorectal carcinogenesis, the evolution of molecular classification systems, including their computational and machine-learning foundations and emerging image-based prediction approaches, molecular drivers and the tumor microenvironment (TME) of CRC by summarizing the most investigated molecular pathways involved in CRC pathogenesis and their role as biomarkers for early CRC diagnosis based on the three main molecular mechanisms of colorectal carcinogenesis: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Importantly, emerging evidence reveals that the TME acts as an important factor in driving CRC progression by regulating the immune system through dynamic cellular and molecular interactions. In particular, tumor metabolic reprogramming and microbiota-driven alterations act as major drivers of therapy resistance and immune escape. Combining these mechanisms will enhance biomarker discovery and aid in developing precision medicine for patients with CRC. This review also highlights the regulatory roles of key signaling pathways, including Wnt/β-catenin, epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), and transforming growth factor-beta (TGF-β) signaling, during CRC initiation and progression, while further addressing current targeted therapies and emerging precision-based and experimental therapeutic strategies.