Boosting immunogenic tumour cell death via nanotherapeutic targeting of the Stanniocalcin 1 phagocytosis checkpoint for enhanced cancer immunotherapy.

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.