Macrophage polarization and non-coding RNAs in colorectal cancer progression and metastasis.

Colorectal cancer (CRC) remains a major global health burden, with incidence and mortality rates continuing to rise worldwide. By 2040, CRC cases are projected to reach 3.2 million, driven by complex interactions between genetic, environmental, and lifestyle factors. While the molecular mechanisms of CRC have been extensively studied, increasing evidence highlights the critical role of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in regulating tumor progression, immune evasion, and therapeutic resistance. Recent research reveals that ncRNAs not only influence tumor cell behavior but also modulate the tumor microenvironment (TME), particularly by regulating tumor-associated macrophage (TAM) polarization. The balance between pro-inflammatory M1 and pro-tumorigenic M2 macrophages profoundly affects CRC progression and treatment response. Dysregulated ncRNAs, such as miR-934, lncRNA RPPH1, and circPLCE1, promote M2 polarization and metastasis via PI3K/AKT, NF-κB, and STAT3 signaling pathways, while others like miR-195-5p and lncRNA GAS5 favor M1 polarization and inhibit tumor growth. These molecules act through diverse mechanisms, including exosomal transfer, ceRNA interactions, and transcriptional regulation, forming intricate communication networks between CRC cells and immune components. Understanding these ncRNA-mediated pathways provides novel opportunities for therapeutic intervention, enhancing immunotherapy efficacy, and improving diagnostic precision through circulating exosomal ncRNA biomarkers. Collectively, targeting ncRNA-regulated macrophage polarization holds promise for developing next-generation precision therapies and advancing immunomodulatory strategies in CRC.