2. Academic Validation
  3. Engineered oncolytic virus armed with anti-PCSK9 scFv boosts long-term CD8+ T cell immunity via rewiring MHC-I antigen presentation

Engineered oncolytic virus armed with anti-PCSK9 scFv boosts long-term CD8+ T cell immunity via rewiring MHC-I antigen presentation

  • Cell Rep Med. 2026 Apr 21;7(4):102724. doi: 10.1016/j.xcrm.2026.102724.
Huolun Feng 1,  Yuhan Zhang 2,  Zuda Huang 3,  Jianlong Zhou 2,  Yongfeng Liu 4,  Xiao Xiao 5,  Mingxi Chen 3,  Xin Guo 1,  Jiabin Zheng 2,  Zejian Lyu 2,  Weixian Hu 2,  Deqing Wu 2,  Yong Li 6,  Fan Xing 7
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
  • 2 Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China.
  • 3 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 4 Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China; Department of General Surgery, Longgang Central Hospital of Shenzhen, Shenzhen 518116, China.
  • 5 Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China.
  • 6 Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China. Electronic address: [email protected].
  • 7 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 41923622 DOI: 10.1016/j.xcrm.2026.102724
Abstract

Oncolytic viruses (OVs) are widely studied for their ability to lyse Cancer cells and prime immune responses; however, the immune consequences triggered by OVs remain incompletely understood. Here, we discover that oncolytic VSVΔ51 treatment suppresses the T cell receptor signaling of tumor-infiltrating T cells. Mechanistically, VSVΔ51-infected Cancer cells upregulate PCSK9 secretion, which triggers lysosomal degradation of major histocompatibility complex (MHC)-I in bystander cells. PCSK9 inhibition synergizes with VSVΔ51 treatment to suppress tumor growth in multiple colorectal Cancer models and induce complete regression in a microsatellite-stable (MSS) tumor model. This combination fosters stem-like CD8+ T cells and establishes anti-tumor memory. Engineered VSVΔ51 expressing anti-PCSK9 single-chain variable fragments improves intra-tumor viral replication, sustains anti-tumor CD8+ T cell memory, and enhances anti-PD-1 therapy efficacy. Our results identify the role of PCSK9 in the immunosuppressive feedback following viral Infection and propose a strategy for engineered oncolytic virotherapy.

Keywords

MHC-I; PCSK9; immune memory; oncolytic virus.

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