Effect of CF33-hNIS oncolytic virus on M2 macrophages and tumor microenvironment in gastric cancer.

作者：Zhifang Zhang, Annie H. Yang, Shyambabu Chaurasiya, Anthony K. Park, Yoya Vashi, Jennifer Cillis, Jianming Lu, Sang-In Kim, Yuman Fong, Yanghee Woo · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.2_suppl.432 · 研究领域：Virus-based gene therapy research、Cancer Research and Treatments、Immune cells in cancer

432 Background: Gastric cancer peritoneal metastasis (GCPM) has limited therapeutic options and dismal prognosis. Oncolytic virotherapy (OVT) efficacy is critically shaped by its interaction with TAMs. CF33, a novel chimeric orthopoxvirus, demonstrates cytotoxicity against gastric cancer (GC) cells, but its effects on M2-polarized tumor-associated macrophages (TAMs)—the dominant immune-suppressive component of the peritoneal tumor microenvironment (TME)—remain poorly defined. Methods: Patient-derived ascitic cells from GCPM were treated with CF33-GFP and analyzed by flow cytometry. Human PBMC-derived M2 macrophages were exposed to CF33-OVs to assess viral infection/replication, cytotoxicity, death pathways, and M2→M1 phenotypic switching, using annexin V/PI staining, microscopy, MTS assays, TEM, western blotting, RNA-seq, cytokine multiplexing, and migration assays. In vivo effects were validated in a syngeneic mouse model of GCPM (ACKPY3944), with TAM modulation assessed by flow cytometry and immunohistochemistry. Results: CF33-OVs selectively infected and replicated in M2 macrophages, inducing CELL death through intrinsic apoptotic and autophagic pathways, with activation of p-TBK1, p-Akt, p38 MAPK, and CDK4/6 signaling. RNA-seq revealed reprogramming of M2 macrophages toward an M1 phenotype, accompanied by upregulation of pro-inflammatory cytokines/chemokines and enhanced immune cell migration. Ex vivo, CF33-OVs eliminated TAMs in patient-derived ascites, and in vivo, CF33...