Abstract
Eliciting calreticulin (CRT) surface exposure is essential for triggering immunogenic cell death (ICD). However, stanniocalcin 1 (STC1) suppresses CRT translocation by sequestering it within mitochondria, limiting ICD induction in tumours. Here, we show that silencing STC1 enhances CRT surface exposure in Lewis lung carcinoma (LLC) cells when combined with paclitaxel (PTX), converting dying tumour cells into an in-situ vaccine that drives immunoprevention of tumour growth. To maximize this therapeutic synergy, we engineered a nanoplatform co-delivering siSTC1 and PTX, in which PTX is covalently conjugated to a sphingolipid and siSTC1 is electrostatically encapsulated (siSTC1/LNP-PTX). This system improves pharmacokinetics, synchronizes co-delivery to tumours, and enhances intratumoral exposure. Consequently, it amplifies CRT expression, promotes antigen-presenting cell-mediated phagocytosis and antigen presentation, and elicits robust cytotoxic T cell responses in LLC models. Moreover, siSTC1/LNP-PTX sensitizes tumours to PD-1 blockade. Our nanosystem, which unlocks ICD potential by silencing STC1, represents a paradigm-shifting approach to cancer immunotherapy.
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Acknowledgements
This work was supported in part by Startup and Retention Funds from the R. Ken Coit College of Pharmacy at The University of Arizona (UArizona), a PhRMA Foundation Faculty Starter Grant in Drug Delivery, UArizona Comprehensive Cancer Centre (UACCC) Internal Pilot and Within Reach Awards, and the National Institutes of Health (NIH) grants (R35GM147002 and R01CA272487). We acknowledge the use of Mass Spectrometry in Analytical and Biological Mass Spectrometry Core Facility at the UArizona BIO5 Institute; the UArizona Translational Bioimaging Resource Core for the Lago live animal imaging; Tissue Acquisition and Cellular/Molecular Analysis Shared Resource (TACMASR) at UArizona Cancer Centre (UACC) for the immunohistochemistry staining. We thank Doug Cromey, the co-manager of the University of Arizona Imaging Cores-Optical Core Facility, for providing trainings and supports; and the Flow Cytometry Immune Monitoring Shared Resource (FCIMSR) core for flow cytometry studies at UACC, which are supported by NIEHS P30 ES006694 and NCI P30 CA023074.
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J.L. has applied for patents related to Sphingomyelin-derived drug nanotechnology. The other authors have no competing interests.
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Li, W., Wang, Z., Li, M. et al. Boosting immunogenic tumour cell death via nanotherapeutic targeting of the Stanniocalcin 1 phagocytosis checkpoint for enhanced cancer immunotherapy. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72526-1
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DOI: https://doi.org/10.1038/s41467-026-72526-1
