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Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The molecular chaperone HSPA8 is classically recognized for its role in protein homeostasis, and while its upregulation correlates with poor prognosis in triple-negative breast cancer (TNBC), whether HSPA8 exerts non-canonical functions beyond chaperoning remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Through integrative transcriptomic profiling, RNA immunoprecipitation (RIP), isoform-specific rescue experiments, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      xenograft models, we investigated the functional and mechanistic role of HSPA8 in TNBC pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We unveil a paradigm-shifting function for HSPA8 as a modulator of alternative splicing of the PP2A regulatory subunit gene PPP2R2D, promoting exon 2 retention to favor the full-length PPP2R2D-2 isoform over the truncated PPP2R2D-1. These two isoforms exhibit functionally distinct roles: only PPP2R2D-2 possesses pro-survival activity, whereas PPP2R2D-1 lacks this function. Specifically, PPP2R2D-2 rescues HSPA8 depletion-induced apoptosis by modulating the mitochondrial pathway (BAX\/BCL-2\/cleaved Caspase-3) and restores\n                      <jats:italic>in vivo<\/jats:italic>\n                      tumor growth. Strikingly, this splicing axis also correlates with an immunosuppressive tumor microenvironment, characterized by altered M1\/M2 macrophage marker abundance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings uncover a dual mechanism that simultaneously drives intrinsic survival signaling and is associated with alterations in the tumor immune microenvironment. They transcend the classical chaperone paradigm by establishing HSPA8 as a non-canonical splicing modulator, and the HSPA8-PPP2R2D-2 axis emerges as a critical vulnerability in TNBC, offering a novel therapeutic angle that concurrently targets tumor cell survival and microenvironmental immunosuppression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1941438","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:36:17Z","timestamp":1791174977000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond chaperoning: HSPA8 modulates alternative splicing of PPP2R2D to drive apoptotic evasion and macrophage-associated immune microenvironment remodeling in triple-negative breast cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenting","family":"Xu","sequence":"first","affiliation":[{"name":"Breast Surgery Department, Affiliated Cancer Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingwen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Breast Surgery Department, Affiliated Cancer Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Si","sequence":"additional","affiliation":[{"name":"Breast Surgery Department, Affiliated Cancer Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Yao","sequence":"additional","affiliation":[{"name":"Breast Surgery Department, Affiliated Cancer Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Lei","sequence":"additional","affiliation":[{"name":"Breast Surgery Department, 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