A chemical-genetic system for calreticulin exposure on cancer cells reveals immune-dependent antitumor effects
Abstract
Premortem exposure of calreticulin (CALR) on stressed cancer cells is a cardinal damage-associated molecular pattern that licenses anticancer immunity, yet its immunological sufficiency has remained difficult to define because it normally coincides with cellular stress and cell death. Here, we engineered a chemical-genetic system enabling the conditional, biotin-driven translocation of a membrane-anchored CALR chimera from the endoplasmic reticulum to the plasma membrane, thereby uncoupling CALR exposure from cytotoxicity and other hallmarks of immunogenic cell death. This reductionist approach revealed that isolated CALR surface presentation is sufficient to promote CD91/LRP1-dependent engulfment of tumor cells by conventional dendritic cells, particularly cDC1 and cDC2, leading to enhanced dendritic cell activation, cytotoxic lymphocyte responses, and immunological memory. Across multiple syngeneic tumor models, enforced CALR exposure exerted modest standalone antitumor activity but robustly sensitized poorly immunogenic cancers to cisplatin and PD-1 blockade, culminating in T cell-dependent tumor eradication and durable protective immunity. Remarkably, concurrent inhibition of the CD47-SIRPα axis facilitated complete tumor eradication in all treated animals, highlighting the functional cooperation between eat-me and don't-eat-me signals in orchestrating antigen presentation and adaptive immune priming. These findings further suggest that maximizing the therapeutic activity of CD47 blockade may require concomitant reinforcement of pro-phagocytic signals such as CALR exposure, providing a conceptual framework for the rational design of next-generation combination immunotherapies. Collectively, these findings establish surface-exposed CALR as a cell-autonomous immunogenic signal with instructive activity for dendritic cell-mediated cross-priming and provide a tractable platform to mechanistically deconvolute immunogenic stress responses, with immediate implications for the rational design of combinatorial chemo-and immunotherapeutic regimens in preclinical and potentially clinical oncology.
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BibTeX
@article{zhao2026chemicalgenetic,
title = {{A chemical-genetic system for calreticulin exposure on cancer cells reveals immune-dependent antitumor effects}},
author = {Liwei Zhao and Misha Mao and Zhe Shen and Yuhong Pan and Ke Chai and Oliver Kepp and Guido Kroemer and Peng Liu},
journal = {Cell Death and Differentiation},
year = {2026},
month = oct,
doi = {10.1038/s41418-026-01891-7},
url = {https://hal.science/hal-05801744v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A chemical-genetic system for calreticulin exposure on cancer cells reveals immune-dependent antitumor effects
AU - Liwei Zhao
AU - Misha Mao
AU - Zhe Shen
AU - Yuhong Pan
AU - Ke Chai
AU - Oliver Kepp
AU - Guido Kroemer
AU - Peng Liu
PY - 2026
DA - 2026/10/15
JO - Cell Death and Differentiation
DO - 10.1038/s41418-026-01891-7
UR - https://hal.science/hal-05801744v1
AB - Premortem exposure of calreticulin (CALR) on stressed cancer cells is a cardinal damage-associated molecular pattern that licenses anticancer immunity, yet its immunological sufficiency has remained difficult to define because it normally coincides with cellular stress and cell death. Here, we engineered a chemical-genetic system enabling the conditional, biotin-driven translocation of a membrane-anchored CALR chimera from the endoplasmic reticulum to the plasma membrane, thereby uncoupling CALR exposure from cytotoxicity and other hallmarks of immunogenic cell death. This reductionist approach revealed that isolated CALR surface presentation is sufficient to promote CD91/LRP1-dependent engulfment of tumor cells by conventional dendritic cells, particularly cDC1 and cDC2, leading to enhanced dendritic cell activation, cytotoxic lymphocyte responses, and immunological memory. Across multiple syngeneic tumor models, enforced CALR exposure exerted modest standalone antitumor activity but robustly sensitized poorly immunogenic cancers to cisplatin and PD-1 blockade, culminating in T cell-dependent tumor eradication and durable protective immunity. Remarkably, concurrent inhibition of the CD47-SIRPα axis facilitated complete tumor eradication in all treated animals, highlighting the functional cooperation between eat-me and don't-eat-me signals in orchestrating antigen presentation and adaptive immune priming. These findings further suggest that maximizing the therapeutic activity of CD47 blockade may require concomitant reinforcement of pro-phagocytic signals such as CALR exposure, providing a conceptual framework for the rational design of next-generation combination immunotherapies. Collectively, these findings establish surface-exposed CALR as a cell-autonomous immunogenic signal with instructive activity for dendritic cell-mediated cross-priming and provide a tractable platform to mechanistically deconvolute immunogenic stress responses, with immediate implications for the rational design of combinatorial chemo-and immunotherapeutic regimens in preclinical and potentially clinical oncology.
SN - 1350-9047
SN - 1476-5403
ER -