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U.S.A."],"published-print":{"date-parts":[[2025,9,23]]},"abstract":"<jats:p>Wnt signaling plays a crucial role for many developmental processes. It is also pivotal in the generation and limited treatment outcomes of glioblastoma (GBM). Here, we identified Wnt7b, which is markedly upregulated in GBM patients, as a determinant of resistance to immune checkpoint blockers (\u03b1PD1; anti-Programmed Cell Death Protein 1) in a clinically relevant, \u03b1PD1-resistant GBM murine model with abundant stem cells. We observed that increased levels of Wnt7b and \u03b2-catenin correlated with the resistance to \u03b1PD1. Treatment combining a porcupine inhibitor WNT974 with \u03b1PD1 reprogrammed the immune suppressive tumor microenvironment (TME) to bolster antitumor immune responses and extended the survival of mice bearing orthotopic GBM, with 25% long-term survivors. Our causal studies revealed that WNT974 potentiated \u03b1PD1 therapy by the expansion of antigen presenting DC3-like dendritic cells (DCs). Additionally, WNT974 combination with \u03b1PD1 was associated with a reduction in immune suppressive granulocytic myeloid-derived suppressor cells (MDSCs), an increase in the Ki67+CD8\/Ki67+regulatory T cells (Treg) ratio, tilting the CD8:Treg balance in the TME toward antitumor immune response, and more pronounced GrzB+CD8+ effector T cells. Conversely, an increase in monocytic MDSCs and phosphorylation of pro-oncogenic proteins was associated with resistance to the combination therapy. Collectively, our preclinical findings provide a strong rationale to test Wnt7b\/\u03b2-catenin inhibition with \u03b1PD1 therapy in GBM patients with elevated Wnt7b\/\u03b2-catenin signaling.<\/jats:p>","DOI":"10.1073\/pnas.2414941122","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T19:08:34Z","timestamp":1757963314000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1013-6134","authenticated-orcid":false,"given":"Shanmugarajan","family":"Krishnan","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Edwin L. 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