Li Wenke, Xu Menghui, Cheng Mo, Wei Jing, Zhu Lin, Deng Yu, Guo Fukun, Bi Feng, Liu Ming
Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu, China.
Cancer Med. 2025 Jul;14(14):e71065. doi: 10.1002/cam4.71065.
Immunotherapy combined with chemotherapy has become the standard treatment for HER2-negative gastric cancer (GC), but its clinical benefits remain limited, with a median progression-free survival (mPFS) of 6-8 months and median overall survival (mOS) of 15-18 months. These outcomes are particularly poor in patients with CPS < 1. The marked heterogeneity of GC, along with primary and secondary resistance, presents significant clinical challenges and underscores the urgent need for novel therapeutic strategies.
To address these limitations, several combination therapies are being explored. Anti-VEGF therapy combined with immune checkpoint inhibitors (ICIs) has shown synergistic effects by enhancing immune cell infiltration and reducing tumor-mediated immunosuppression, thereby improving response rates and survival. Radiotherapy combined with ICIs also holds promise, with low-dose radiation remodeling the tumor microenvironment and high-dose radiation inducing immunogenic cell death. Other potential combinations include PD-1/PD-L1 inhibitors paired with targeted therapies against HER2, FGFR2, DKK1, PARP, LSD1, HDAC, and other emerging targets. Novel approaches such as hyperbaric oxygen therapy, oncolytic viruses, metabolic modulators, and fecal microbiota transplantation are also under investigation to further enhance immune responses.
These multimodal strategies represent a promising shift toward personalized, mechanism-driven immunotherapy sensitization. By targeting diverse pathways to overcome immune resistance, they aim to reshape the tumor microenvironment, restore immune responsiveness, and improve outcomes in GC. While many remain in early-stage development, accumulating evidence supports their potential. Future research should prioritize optimizing combination regimens, clarifying resistance mechanisms, and identifying predictive biomarkers through multi-omics and artificial intelligence to enable more precise, individualized immunotherapy.
免疫疗法联合化疗已成为HER2阴性胃癌（GC）的标准治疗方法，但其临床益处仍然有限，无进展生存期（mPFS）中位数为6 - 8个月，总生存期（mOS）中位数为15 - 18个月。在CPS < 1的患者中，这些结果尤其差。GC的显著异质性以及原发性和继发性耐药带来了重大的临床挑战，并突出了对新型治疗策略的迫切需求。
为解决这些局限性，正在探索几种联合疗法。抗血管内皮生长因子（VEGF）疗法联合免疫检查点抑制剂（ICI）已显示出协同作用，通过增强免疫细胞浸润和减少肿瘤介导的免疫抑制，从而提高缓解率和生存率。放疗联合ICI也具有前景，低剂量放疗可重塑肿瘤微环境，高剂量放疗可诱导免疫原性细胞死亡。其他潜在的联合方案包括将PD - 1/PD - L1抑制剂与针对HER2、FGFR2、DKK1、PARP、LSD1、HDAC及其他新兴靶点的靶向疗法配对。高压氧疗法、溶瘤病毒、代谢调节剂和粪便微生物群移植等新方法也在研究中，以进一步增强免疫反应。
这些多模式策略代表了向个性化、机制驱动的免疫疗法致敏的有前景的转变。通过针对不同途径克服免疫抵抗，它们旨在重塑肿瘤微环境，恢复免疫反应性，并改善GC的治疗结果。虽然许多仍处于早期开发阶段，但越来越多的证据支持它们的潜力。未来的研究应优先优化联合方案，阐明耐药机制，并通过多组学和人工智能识别预测性生物标志物，以实现更精确、个性化的免疫疗法。
