2. Academic Validation
  3. Dissecting genetic and immune drivers of heterogeneous responses to neoadjuvant immunochemotherapy in gastric cancer

Dissecting genetic and immune drivers of heterogeneous responses to neoadjuvant immunochemotherapy in gastric cancer

  • Cancer Cell. 2026 Apr 13;44(4):809-830.e11. doi: 10.1016/j.ccell.2026.01.015.
Qi Zhao 1,  Runjie Huang 2,  Chaoye Wang 3,  Jiajia Hu 4,  Runcong Nie 5,  Rui Jian 5,  Yingnan Wang 2,  Dongfang Wang 6,  Chengcai Liang 5,  Yanxing Chen 2,  Yukun Chen 2,  Chenyi Wu 2,  Jinling Zhang 7,  Jiaying Chen 2,  Nan An 5,  Ying Jin 2,  Wenlong Guan 2,  Zixian Wang 2,  Yuanfang Li 5,  Xiaowei Sun 5,  Yingbo Chen 5,  Wei Wang 5,  Haibo Qiu 5,  Zhiwei Zhou 5,  Feng Wang 2,  Rui-Hua Xu 8,  Shuqiang Yuan 9
Affiliations

Affiliations

  • 1 Department of Experimental Research, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China.
  • 2 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
  • 3 Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, P.R. China.
  • 4 Department of Experimental Research, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
  • 5 Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
  • 6 Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, P.R. China.
  • 7 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China.
  • 8 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China; Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Electronic address: [email protected].
  • 9 Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Electronic address: [email protected].
PMID: 41720086 DOI: 10.1016/j.ccell.2026.01.015
Abstract

Although neoadjuvant immunochemotherapy (nICT) improves gastric Cancer (GC) outcomes, resistance remains a challenge, highlighting the need for better patient selection and strategies to overcome resistance. Here, we analyze 110 patients with GC before and after nICT or chemotherapy (nCT) from the NEOSUMMIT-01 trial using multi-omic Sequencing followed by functional validation. We identify five tumor microenvironment ecotypes (EC1-5) linked to therapy. nICT achieves response in EC1 (T cell activation), EC2 (tertiary lymphoid structures), and EC3 (vascular normalization), but not in EC4 (extracellular matrix organization) and EC5 (immunosuppressive macrophage enrichment). Notably, nICT resistance in EC5 is mediated by the interaction between APOA1+ tumor cells and TREM2+ macrophages. Additionally, we reveal multiple biomarkers associated with nICT efficacy, including SBS19, HLA-B∗15:02, FDXR expression, and FGFR pathway activity, and provide a multi-omic stratification model for treatment response-based patient stratification. This study provides mechanistic insights into nICT in GC, informs therapeutic decisions, and reveals potential targets.

Keywords

gastric cancer; immunochemotherapy; multi-omics; neoadjuvant anti-PD-1 treatment; single-cell analysis; treatment resistance.

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