{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:12:58Z","timestamp":1789193578233,"version":"build-2803163510"},"reference-count":61,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"unspecified","delay-in-days":18,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373895"],"award-info":[{"award-number":["82373895"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,11,2]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immunotherapy resistance in microsatellite-stable colorectal cancer (CRC) remains a major therapeutic challenge. Recent strategies to overcome the immunosuppressive tumor microenvironment have focused on reactivating innate immune pathways, particularly the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis, which links cytosolic DNA sensing to proinflammatory cytokine production and T cell activation. Although STING agonists show promise, their clinical application is limited by poor drug stability and cytokine storms triggered by excessive STING activation. This study establishes valosin-containing protein (VCP\/p97) as a druggable target to potentiate cGAS-STING-driven antitumor immunity, offering a promising therapeutic strategy to overcome immunotherapy resistance in CRC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Bioinformatics analysis and compound screening were conducted to find potential regulators of the cGAS-STING pathway. Western blotting, co-immunoprecipitation, immunofluorescence staining, real-time PCR, molecular docking, and RNA sequencing (RNA-seq) were performed to identify VCP as a new regulator of STING proteostasis. Wild-type\/\n                      <jats:italic>\n                        Sting1\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      C57BL\/6J mice with MC38 tumors and BALB\/c mice with CT26 tumors were employed to evaluate the in vivo therapeutic effects of the VCP inhibitor and STING agonist\/chemotherapy\/immunotherapy combination. Flow cytometry, ELISA, immunofluorescence staining, and RNA-seq were performed to analyze the effectiveness of these interventions in remodeling the tumor microenvironment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we determined the importance of the cGAS-STING pathway activity in macrophages for antitumor immunity by bioinformatics analysis and identified VCP as a critical negative regulator of STING through analyzing genome-wide CRISPR screening data and performing pharmacological validation. Mechanistically, VCP directly interacts with STING and modulates its protein stability. Pharmacological inhibition of VCP using CB-5083 stabilized STING protein, increased the pool of endoplasmic reticulum (ER)-localized STING, amplified STING agonist-induced signaling, and synergized with STING agonists to suppress tumor growth in murine models. Furthermore, CB-5083 significantly enhanced the antitumor efficacy of chemotherapy and immunotherapy in CRC models, while remodeling the immune microenvironment by increasing CD86+ macrophages\u2009and cytotoxic CD8+ T\u2009cell infiltration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study identifies VCP as a new regulator of STING proteostasis and provides a novel strategy to boost antitumor immunity by pharmacologically increasing ER-resident STING via VCP inhibition, offering a clinically actionable avenue to improve CRC therapy.<\/jats:p>\n                  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