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Preclinical studies indicate that targeting abnormal neoangiogenesis by inhibiting vascular endothelial growth factor receptor (VEGFR) can alter the TME, thereby promoting T cell infiltration and increasing tumor immunogenicity. The REGOMUNE study, a phase II clinical trial, assessed the therapeutic combination of regorafenib, a multityrosine kinase inhibitor that targets VEGFR2 and the PD-L1 blocker avelumab, in individuals with advanced \u201ccold\u201d STS characterized by a lack of mature tertiary lymphoid structures (mTLS). Forty-nine mTLS-negative STS patients were enrolled, including leiomyosarcoma (45%), synovial sarcoma (18%), and other subtypes. The objective response rate was 11.0% (95% CI: 4.0% - 22.0%), with median progression-free survival and overall survival of 1.8 months (95% CI, 1.7\u20133.5 months) and 15.1 months, respectively. Frequent adverse events included grade 1 or 2 palmar-plantar erythrodysesthesia, fatigue, and diarrhea. On-treatment multiplex immunofluorescence analysis revealed significant increases in CD8\u2009+\u2009T cell and B cell infiltration and PD1 expression on immune cells. Plasma analysis indicated significant upregulation of soluble PD-L1 (sPD-L1) levels and tryptophan consumption. Overall, these results indicate that anti-angiogenic therapy modulates the tumor microenvironment in patients with cold STS and highlight the need for complementary strategies to enhance the functional activity of immune cells in this particular setting. Clinical trial registration number: NCT03475953<\/jats:p>","DOI":"10.1038\/s41392-025-02278-9","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T06:41:19Z","timestamp":1751006479000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Reshaping the tumor microenvironment of cold soft-tissue sarcomas with anti-angiogenics: a phase 2 trial of regorafenib combined with avelumab"],"prefix":"10.1038","volume":"10","author":[{"given":"Maud","family":"Toulmonde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Gu\u00e9gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7582-3365","authenticated-orcid":false,"given":"Mariella","family":"Spalato-Ceruso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibaud","family":"Valentin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rastilav","family":"Bahleda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Peyraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Rey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mich\u00e8le","family":"Kind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coralie","family":"Cantarel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Bellera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7733-7806","authenticated-orcid":false,"given":"Lucile","family":"Vanhersecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alban","family":"Bessede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8540-5351","authenticated-orcid":false,"given":"Antoine","family":"Italiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"2278_CR1","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1186\/s13045-024-01580-3","volume":"17","author":"M Spalato-Ceruso","year":"2024","unstructured":"Spalato-Ceruso, M., Ghazzi, N. 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J.P.G., C.R., and A.B.: employees of Explicyte. The other co-authors have nothing to disclose. The other authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the Comit\u00e9 de Protection des Personnes (CPP) Sud-Ouest et Outre Mer III (Bordeaux, France) according to good clinical practices and applicable laws and regulations. All methods were performed in accordance with the relevant guidelines and regulations. All patients provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"202"}}