2. Academic Validation
  3. Regorafenib enhances anti-PDCD1/PD-1 therapeutic efficacy in colorectal cancer by promoting SQSTM1/p62-mediated CD274/PD-L1 degradation

Regorafenib enhances anti-PDCD1/PD-1 therapeutic efficacy in colorectal cancer by promoting SQSTM1/p62-mediated CD274/PD-L1 degradation

  • Autophagy. 2026 Jun;22(6):1203-1220. doi: 10.1080/15548627.2026.2629288.
Ming Zhu 1 2,  Yinjun He 2 3,  Siqin Lei 4,  Xuan Lai 2,  Chaoyi Chen 5,  Kehong Ye 2,  Dianyang Li 6,  Honghe Zhang 2,  Maode Lai 2,  Weiqin Jiang 1
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery and Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China.
  • 2 Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 3 Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5 Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 6 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
PMID: 41655134 DOI: 10.1080/15548627.2026.2629288
Abstract

Despite the clinical success of PDCD1/PD-1 and CD274/PD-L1 immune checkpoint blockade in multiple cancers, its efficacy in colorectal Cancer (CRC) remains limited. Here, we report that the combination of the tyrosine kinase inhibitor regorafenib with PDCD1 blockade enhances anti-tumor immunity in CRC, both in clinical observations and preclinical models. Mechanistically, regorafenib acts as a molecular glue, directly promoting the interaction between CD274 and the selective Autophagy receptor SQSTM1/p62, leading to SQSTM1-mediated autophagic degradation of CD274 and restoration of T cell-mediated cytotoxicity. In summary, these findings identify a previously unrecognized role of regorafenib in modulating tumor immune evasion and provide a mechanistic rationale for its combination with PDCD1 inhibitors in CRC treatment.Abbreviations: 3-MA: 3-methyladenine; ATG5: Autophagy related 5; ATG7: Autophagy related 7; CD274/PD-L1: CD274 molecule; CHX: cycloheximide; co-IP: co-immunoprecipitation; CQ: chloroquine; CRC: colorectal cancer; CTLs: cytotoxic T cells; ECD: extracellular domain; GZMB: granzyme B; ICD: intracellular domain; IF: immunofluorescence; IFNG/IFN-γ: interferon gamma; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; mCRC: metastatic colorectal cancer; mIF: multiplex immunofluorescence; MSS: microsatellite stable; ORRs: objective response rates; PDCD1/PD-1: programmed cell death 1; PDCD1i: PDCD1 inhibitor; pMMR: mismatch repair-proficient; PROTACs: proteolysis-targeting chimeras; SPR: surface plasmon resonance; SQSTM1/p62: sequestosome 1; TKI: multikinase inhibitor; TME: tumor microenvironment; WB: western blot; WT: wild-type.

Keywords

Antitumor immunity; PD-L1; molecular glue; p62; protein degradation; regorafenib.

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