Chromosomal Instability Regulates the Tumor Immune Microenvironment: From Fundamental Mechanisms to Therapeutic Breakthroughs in Colorectal Cancer Treatment

染色体不稳定性(Chromosomal instability, CIN)作为实体瘤的主要特征之一，通过驱动基因组异质性、微核形成及细胞质双链DNA (dsDNA)累积等多种复杂的机制对肿瘤免疫微环境(TME)的形成及其对免疫应答造成一定的影响。近年来研究揭示了CIN的“两面性”：即中等水平的CIN能使肿瘤更好地适应肿瘤微环境的变化，而过度的CIN会导致遗传灾难和细胞死亡，触发细胞焦亡并释放损伤相关分子模式(DAMPs)，提高抗肿瘤免疫识别。然而，CIN与免疫微环境之间的关系目前仍然是一个复杂的网络，特别是在结直肠癌(CRC)中，CIN相关分子机制(如YY2/BUB1B轴)通过释放肿瘤新抗原和促炎因子(IL-1、IFNγ)，重塑TME并克服微卫星稳定(MSS)型CRC的免疫治疗抵抗。此外，联合丝氨酸/苏氨酸激酶(AURK)抑制剂与免疫检查点阻断、或通过代谢重编程靶向糖酵解和DNA修复通路，为克服CRC治疗耐药提供了新策略。本文整合基础机制与临床转化视角，提出靶向CIN-TME交互网络的联合治疗策略，为优化结直肠癌免疫治疗及拓展适应症提供理论依据和应用前景。Chromosomal instability (CIN), as one of the main features of solid tumors, affects the formation of tumor immune microenvironment (TME) and its impact on immune response through various complex mechanisms, such as driving genomic heterogeneity, micronucleus formation and cytoplasmic double-stranded DNA (dsDNA) accumulation. Recent studies have revealed the “two sides” of CIN, i.e., moderate levels of CIN enable tumors to better adapt to changes in the tumor microenvironment, whereas excessive CIN leads to genetic catastrophe and cell death, triggers cellular paralysis and releases damage-associated molecular patterns (DAMPs), and enhances anti-tumor immune recognition. However, the relationship between CIN and the immune microenvironment currently remains a complex network, especially in colorectal cancer (CRC), where CIN-associated molecular mechanisms (e.g., the YY2/BUB1B axis) remodel the TME and overcome immunotherapeutic resistance in microsatellite-stabilized (MSS)-type CRC through the release of tumor neoantigens and pro-inflammatory factors (IL-1, IFNγ). In addition, combining serine/threonine kinase (AURK) inhibitors with immune checkpoint blockade, or targeting glycolytic and DNA repair pathways through metabolic reprogramming, provides new strategies to overcome CRC treatment resistance. In this review, we integrate basic mechanisms and clinical translational perspectives to propose a combination therapy strategy targeting the CIN-TME interaction network, which provides a theoretical basis and application prospect for optimizing colorectal cancer immunotherapy and expanding indications.