Background: Metastatic colorectal cancer (mCRC) with TP53 gene mutations, which are commonly found in tumors that are microsatellite stable (MSS) and not prone to genetic errors seen in some cancers, is associated with aggressive cancer behavior and poor outcomes. While MSI-high (MSI-H, referring to high levels of gene instability) disease benefits markedly from PD-1-based immunotherapy (drugs that inhibit the PD-1 protein on immune cells), TP53-mutated MSS tumors rarely receive immune checkpoint inhibitors (ICIs, drugs that help immune cells attack cancer) outside of trials and often only in later lines of therapy. Objective: We aimed to synthesize translational and clinical evidence regarding the effects of early rationale-driven immunotherapy combinations on survival outcomes, in TP53-mutated metastatic colorectal cancer, with a focus on practical clinical implications. Methods: This narrative review was conducted in accordance with SANRA criteria. Literature searches were performed in PubMed/MEDLINE, Scopus, and Web of Science (2010–2025). Relevant ESMO and NCCN guidelines and key references were also reviewed. Results: In KEYNOTE-177 study (MSI-H/dMMR), pembrolizumab improved PFS (HR 0.60) and showed durable OS with >5-year follow-up. CheckMate-142 reported sustained activity with nivolumab ± ipilimumab. Preclinical/early clinical data in MSS/TP53 suggest that ICIs may become effective when combined with priming (chemo/DDR) and vascular normalization (anti-VEGF), particularly in subsets with elevated TMB. The randomized ROME trial supports the clinical utility of genomically matched, NGS-guided strategies. Conclusions: A precision approach integrating TP53 status, TMB, and TME modulation could extend the immunotherapy benefit beyond MSI-H to TP53-mutated MSS mCRC; prospective first-line trials are warranted.
背景：携带TP53基因突变的转移性结直肠癌（mCRC）通常表现为微卫星稳定（MSS）表型，且不具备某些癌症中常见的遗传错误易感性，这类肿瘤往往具有侵袭性强、预后差的特点。虽然微卫星高度不稳定（MSI-H）疾病能从基于PD-1的免疫治疗（抑制免疫细胞PD-1蛋白的药物）中显著获益，但TP53突变的MSS肿瘤在临床试验外很少接受免疫检查点抑制剂（ICIs，帮助免疫细胞攻击癌细胞的药物），且多用于后线治疗。目的：本研究旨在整合转化医学与临床证据，探讨早期基于生物学机制的联合免疫治疗对TP53突变转移性结直肠癌生存结局的影响，重点关注临床实践意义。方法：本叙述性综述遵循SANRA标准撰写。文献检索覆盖PubMed/MEDLINE、Scopus和Web of Science数据库（2010-2025年），同时参考了ESMO与NCCN指南及相关重要文献。结果：KEYNOTE-177研究（MSI-H/dMMR患者）显示帕博利珠单抗可改善无进展生存期（HR 0.60），长期随访显示其总生存获益可持续超过5年。CheckMate-142研究报道纳武利尤单抗±伊匹木单抗具有持续疗效。MSS/TP53肿瘤的临床前及早期临床数据表明，免疫检查点抑制剂与化疗/DDR抑制剂等免疫启动策略及抗VEGF血管正常化治疗联用可能产生疗效，尤其在肿瘤突变负荷（TMB）升高的亚群中。随机ROME试验证实了基因组匹配、NGS指导策略的临床实用性。结论：整合TP53状态、TMB及肿瘤微环境调控的精准治疗策略，有望将免疫治疗获益从MSI-H人群拓展至TP53突变的MSS型转移性结直肠癌，有必要开展前瞻性一线治疗试验加以验证。
Can TP53, TMB and TME Expand the Immunotherapy Benefit in Metastatic Colorectal Cancer?
肿瘤(癌症)患者之家