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The Application of Salidroside@T-exo Regulated by the PI3K/AKT/mTOR Pathway in the Remodeling of the Immune Microenvironment in Breast Cancer

ABSTRACT: Breast cancer (Breast Cancer, BC) patients often face the issue of acquired resistance during PD-1 immunotherapy, which significantly limits the efficacy and durability of treatment. Research indicates that the tumor immune microenvironment is closely linked to the development of resistance. To address this challenge, this study aims to regulate the PI3K/AKT/mTOR signaling pathway by using Salidroside-loaded oligopeptide-modified tumor stem cell-derived exosomes (Salidroside@T-exo), thereby reshaping the immune microenvironment of breast cancer and reversing PD-1 immunotherapy resistance. We modified the oligopeptide TMTP1 onto the surface of tumor stem cell exosomes and introduced Salidroside via electroporation to prepare Salidroside@T-exo. The experiment involved in vitro construction of a MA782/5s-8101 PD-1-resistant cell model, combined with high-throughput sequencing, proteomics, and metabolomics analyses, to investigate the effects of Salidroside@T-exo on tumor cell proliferation, metabolism, and the immune microenvironment. The results demonstrated that Salidroside@T-exo significantly inhibited the activity of the PI3K/AKT/mTOR signaling pathway, enhanced T cell proliferation and tumor cell-killing capacity, reshaped the immune microenvironment, and successfully reversed PD-1 resistance. Our study provides an innovative therapeutic strategy for breast cancer, which may help improve the efficacy of immunotherapy.

ORGANISM(S): Mus Musculus

SUBMITTER: Jun Qian

PROVIDER: PXD070267 | iProX | Tue Nov 04 00:00:00 GMT 2025

REPOSITORIES: iProX

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Study on the Molecular Mechanism of Salidroside@T-exo Inducing Breast Cancer Immune Microenvironment Remodeling and Reversing Acquired Resistance to Immunotherapy by Regulating the PI3K/AKT/mTOR Signaling Pathway

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Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

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