肿瘤细胞治疗研究
英文原题：Next-generation precision oncology in microsatellite stable colorectal cancer: integrated targeting beyond RAS and RAF.
结直肠癌（CRC）的治疗格局随着分子亚型的识别而不断演变，这些亚型包括错配修复缺陷/微卫星高度不稳定、POLE突变、RAS/BRAF改变以及HER2扩增，使得精准治疗和免疫检查点抑制剂可用于特定人群。
结直肠癌（CRC）的治疗格局随着分子亚型的识别而不断演变，包括错配修复缺陷/微卫星高度不稳定、POLE突变、RAS/BRAF改变以及HER2扩增，使得精准治疗和免疫检查点抑制剂可用于特定人群。然而，大多数微卫星稳定（MSS）肿瘤由于肿瘤异质性、适应性耐药和免疫抑制性肿瘤微环境（TME）而仍然耐药。分子谱分析、空间生物学和免疫表征的进展揭示了经典信号通路之外的脆弱性，促进了抗体药物偶联物（ADC）、双特异性抗体、DNA损伤应答（DDR）靶向、TME导向治疗、细胞治疗和表观遗传调控等新策略的发展。HER2导向的ADC，尤其是trastuzumab deruxtecan，在HER2阳性转移性CRC中显示出具有临床意义的活性，为基于ADC的治疗提供了概念验证。正在研究的其他靶点包括CEACAM5、LGR5、EGFR、HER3、MET、B7-H3和CDH17。双特异性抗体和共刺激激动剂正在开发中，以克服抗原异质性和通路冗余，其中EGFR-MET双特异性抗体amivantamab显示出初步临床疗效。此外，下一代免疫检查点抑制剂和多靶点联合方案旨在重新激活MSS肿瘤中的T细胞应答。靶向CEA和GUCY2C的早期CAR-T 细胞研究证明了可行性和可控的毒性，尽管肿瘤内在和TME屏障仍然存在。新兴策略日益聚焦于调控TME以增强免疫浸润和效应功能，靶向CCR8、TGF-β、腺苷、CSF1R、CXCR1/2、STING和CD47。DDR和表观遗传治疗为增敏耐药肿瘤提供了额外机会。整合的多维生物标志物方法和人工智能驱动的肿瘤及TME特征解读，有望指导个性化治疗、预测耐药，并拓宽靶向和免疫干预在CRC中的获益。
The therapeutic landscape of colorectal cancer (CRC) has evolved with the identification of molecular subtypes, including mismatch repair-deficient/microsatellite instability-high, POLE mutations, RAS/BRAF alterations, and HER2 amplification, enabling use of precision therapies and immune checkpoint inhibitors for selected populations. However, most microsatellite-stable (MSS) tumors remain resistant due to tumor heterogeneity, adaptive resistance, and an immunosuppressive tumor microenvironment (TME). Advances in molecular profiling, spatial biology, and immune characterization have revealed vulnerabilities beyond canonical signaling, facilitating novel strategies such as antibody-drug conjugates (ADCs), bispecific antibodies, DNA damage response (DDR) targeting, TME-directed therapies, cellular therapies, and epigenetic modulation. HER2-directed ADCs, notably trastuzumab deruxtecan, have shown clinically meaningful activity in HER2-positive metastatic CRC, providing proof of concept for ADC-based therapy. Additional targets under investigation include CEACAM5, LGR5, EGFR, HER3, MET, B7-H3, and CDH17. Bispecific antibodies and co-stimulatory agonists are being developed to overcome antigen heterogeneity and pathway redundancy, with the EGFR-MET bispecific antibody amivantamab showing initial clinical efficacy. Moreover, next-generation immune checkpoint inhibitors and multitarget combinations aim to reinvigorate T-cell responses in MSS tumors. Early chimeric antigen receptor T-cell studies targeting CEA and GUCY2C demonstrate feasibility and manageable toxicity, although tumor-intrinsic and TME barriers persist. Emerging strategies increasingly focus on modulating the TME to enhance immune infiltration and effector function, targeting CCR8, TGF-β, adenosine, CSF1R, CXCR1/2, STING, and CD47. DDR and epigenetic therapies offer additional opportunities to sensitize resistant tumors. Integrated, multidimensional biomarker approaches and artificial intelligence-driven interpretation of tumor and TME features are expected to guide personalized therapy, anticipate resistance, and broaden the benefit of targeted and immune-based interventions in CRC.
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