Beyond chaperoning: HSPA8 modulates alternative splicing of PPP2R2D to drive apoptotic evasion and macrophage-associated immune microenvironment remodeling in triple-negative breast cancer.
- 1Breast Surgery Department, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Abstract
Introduction
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.Methods
Through integrative transcriptomic profiling, RNA immunoprecipitation (RIP), isoform-specific rescue experiments, and in vivo xenograft models, we investigated the functional and mechanistic role of HSPA8 in TNBC pathogenesis.Results
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 in vivo tumor growth. Strikingly, this splicing axis also correlates with an immunosuppressive tumor microenvironment, characterized by altered M1/M2 macrophage marker abundance.Discussion
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.
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BibTeX
@article{xu2026beyond,
title = {{Beyond chaperoning: HSPA8 modulates alternative splicing of PPP2R2D to drive apoptotic evasion and macrophage-associated immune microenvironment remodeling in triple-negative breast cancer.}},
author = {Wenting Xu and Qingwen Zheng and Yu Si and Tian Yao and Hao Lei and Yongtao Li},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1941438},
url = {https://europepmc.org/article/MED/42898301},
note = {CC BY},
}
RIS
TY - JOUR
TI - Beyond chaperoning: HSPA8 modulates alternative splicing of PPP2R2D to drive apoptotic evasion and macrophage-associated immune microenvironment remodeling in triple-negative breast cancer.
AU - Wenting Xu
AU - Qingwen Zheng
AU - Yu Si
AU - Tian Yao
AU - Hao Lei
AU - Yongtao Li
PY - 2026
DA - 2026/10/05
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1941438
UR - https://europepmc.org/article/MED/42898301
AB - Introduction 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.Methods Through integrative transcriptomic profiling, RNA immunoprecipitation (RIP), isoform-specific rescue experiments, and in vivo xenograft models, we investigated the functional and mechanistic role of HSPA8 in TNBC pathogenesis.Results 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 in vivo tumor growth. Strikingly, this splicing axis also correlates with an immunosuppressive tumor microenvironment, characterized by altered M1/M2 macrophage marker abundance.Discussion 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.
SN - 2234-943X
ER -