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Because therapeutic efficacy is shaped by dynamic virus\u2013tumor\u2013stromal interactions, pharmacologic strategies that reprogram this interface may enhance virotherapy responses. Here, we investigate whether targeting tumor stress and survival pathways with triptolide and its prodrug Minnelide can enhance the oncolytic efficacy of measles virus in colorectal cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The in vitro effects of CD46 targeted (MV-GFP) and dual targeted (MV-CD46-muPA) oncolytic MV, alone and with Triptolide were assessed in human CRC cell lines. Mechanistic studies included gene expression analysis, functional proteomics, and western blotting. In vivo efficacy of MV-CD46-muPA combined with Minnelide was evaluated in HT29 and HCT116 xenografts. Biological effects were further characterized using transcriptomic profiling (RNA-seq), targeted gene expression (NanoString), and histological analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Triptolide enhanced MV mediated oncolysis in vitro, particularly in BRAF V600E mutant CRC cell lines, and modulated key cancer pathways including AKT, apoptosis and metabolism. In vivo, Minnelide significantly improved the efficacy of systemically administered MV-CD46-muPA in human CRC xenografts, with greater effects in BRAF mutant (HT29) models. The combination modulated cell cycle, metabolism, and survival associated genes, promoted apoptosis, and improved intratumoral viral distribution. These molecular effects resulted in reduced tumor cell proliferation (Ki67), decreased angiogenesis (CD31), and increased apoptosis (TUNEL) relative to single agents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Triptolide and Minnelide significantly enhance the oncolytic efficacy of measles virus in colorectal cancer, particularly in BRAF-mutant tumors in vivo, through reprogramming of virus\u2013tumor\u2013stromal interactions. This reprogramming arises from coordinated modulation of survival, metabolic, and stromal signaling pathways and is accompanied by improved intratumoral viral distribution. These findings position virus\u2013tumor\u2013stromal crosstalk as a central mechanistic axis of virotherapy response and provide a strong rationale for the translational and clinical development of rational virus\u2013drug combination strategies in colorectal cancer and other malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03749-9","type":"journal-article","created":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T08:06:13Z","timestamp":1780733173000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacologic reprogramming of virus-tumor crosstalk enhances measles virus antitumor activity in BRAF mutant colorectal cancer models"],"prefix":"10.1186","volume":"45","author":[{"given":"Valery","family":"Chavez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Montero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngoc Huong Giang","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina Merchan","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuguang","family":"Ban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rimpi","family":"Khurana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Ceccarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime R.","family":"Merchan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"issue":"1","key":"3749_CR1","first-page":"e70043","volume":"76","author":"RL Siegel","year":"2026","unstructured":"Siegel RL, et al. 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