Abstract Objective: Immunotherapy resistance remains a significant clinical challenge in the treatment of triple-negative breast cancer (TNBC). Cancer-associated fibroblasts (CAFs)-mediated induction of an immunosuppressive tumor microenvironment (TME) is a key contributing mechanism, but the underlying molecular regulatory networks are inadequately understood. This study aims to systematically elucidate the specific role and molecular mechanisms of PDE3A-expressing CAFs (PDE3A+CAFs) in TNBC immunotherapy resistance, and to assess the safety and therapeutic efficacy of a PDE3A-targeted degrader combined with immunotherapy. Methods: Single-cell sequencing analysis was performed on tumor tissues from TNBC patients undergoing immunotherapy to identify CAF subpopulations associated with immunotherapy resistance. Functional experiments were conducted to evaluate the effects of PDE3A+CAFs on the infiltration of myeloid-derived suppressor cells (MDSCs) and the function of T cells. Mechanistic investigations included assessments of the interaction between PDE3A and Cbl-b, the lipid raft translocation of insulin-like growth factor 1 receptor (IGF-1R), and the activation of signal transducer and activator of transcription 3 (STAT3) signaling axis. Additionally, experiments such as chromatin immunoprecipitation (ChIP) were used to verify the regulatory relationship between STAT3 and PDE3A transcription. Results: A specific subpopulation of PDE3A+CAFs was identified as a pivotal mediator of TNBC immunotherapy resistance. Functional experiments confirmed that PDE3A+CAFs significantly promoted MDSC infiltration into TNBC tumors while suppressing T cell function and activity. Mechanistically, PDE3A in CAFs inhibited the negative regulator Cbl-b in a phosphodiesterase-independent manner, thereby facilitating IGF-1R lipid raft translocation and activating the STAT3 signaling axis. Activated STAT3 further recruited MDSCs via upregulating C-X-C motif chemokine ligand 12 (CXCL12) secretion, fostering an immunosuppressive TME. Moreover, STAT3 directly regulated PDE3A transcription, forming a positive feedback loop that sustained pathway activation. Conclusion: PDE3A+CAFs play a critical role in driving TNBC immunotherapy resistance through the PDE3A-Cbl-b-IGF-1R-STAT3-CXCL12 axis and the STAT3-PDE3A positive feedback loop. Targeting PDE3A combined with immunotherapy holds promising potential as a novel therapeutic strategy to overcome immunotherapy resistance and improve TNBC treatment outcomes, providing a solid theoretical foundation for clinical translation. Citation Format: Na Hao. Cancer associated fibroblasts-derived PDE3A promotes lipid raft-regulated IGF-1R translocation and immunotherapy resistance in triple negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6027.
Na Hao (Fri,) studied this question.
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