Reprogramming CAR-T cell function through synthetic cytokine receptors suppresses metastatic progression of TNBC
Abstract
Patient T cells modified with chimeric antigen receptors (CARs) have shown remarkable therapeutic success in previously incurable cancers. However, despite its success in hematological malignancies, CAR-T therapy has shown only modest efficacy in solid tumors. The medical field has focused on developing new molecular designs that enhance CAR-T persistence, prevent exhaustion in the tumor microenvironment (TME), and increase the specificity of the CAR-T cell to various tumor antigens. However, much less effort has been placed on enhancing CAR-T cells' invasion into and migration through the stromal matrix of the TME, where they can elicit tumor-directed cytotoxicity. Here, we engineered CAR-T cells with synthetic cytokine receptors targeting inflammatory cytokines produced by the cells themselves, which increase their speed through collagen I matrices. We show that this enhanced motility is driven by increased CAR-T cell translocation through confined microchannels via cellular deformation, together with elevated migratory speeds in proximity to neighboring cells, suggesting improved responsiveness to local cues. These migration-enhanced CAR-T cells significantly reduce both primary tumor size and distant organ metastasis in triple-negative breast cancer (TNBC) mouse models compared to standard CAR-T cells. These results support molecular design strategies that exploit mechanisms to improve cellular therapies for metastatic solid tumors.
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BibTeX
@misc{hanna2026reprogramming,
title = {{Reprogramming CAR-T cell function through synthetic cytokine receptors suppresses metastatic progression of TNBC}},
author = {Eban A. Hanna and Alice Amitrano and Andre Forjaz and Zhiliang Bai and Chanhong Min and Yoseph Dance and Immanuel Etoh and Bryce Lloyd and Xinyun Jiang and Vasco Queiroga and Praful Nair and Victoria Duarte and Saurabh Joshi and Konstantinos Konstantopoulos and Jude Phillip and Rong Fan and Pei-Hsun Wu and Denis Wirtz},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.760671},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760671v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Reprogramming CAR-T cell function through synthetic cytokine receptors suppresses metastatic progression of TNBC
AU - Eban A. Hanna
AU - Alice Amitrano
AU - Andre Forjaz
AU - Zhiliang Bai
AU - Chanhong Min
AU - Yoseph Dance
AU - Immanuel Etoh
AU - Bryce Lloyd
AU - Xinyun Jiang
AU - Vasco Queiroga
AU - Praful Nair
AU - Victoria Duarte
AU - Saurabh Joshi
AU - Konstantinos Konstantopoulos
AU - Jude Phillip
AU - Rong Fan
AU - Pei-Hsun Wu
AU - Denis Wirtz
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.760671
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.760671v1
AB - Patient T cells modified with chimeric antigen receptors (CARs) have shown remarkable therapeutic success in previously incurable cancers. However, despite its success in hematological malignancies, CAR-T therapy has shown only modest efficacy in solid tumors. The medical field has focused on developing new molecular designs that enhance CAR-T persistence, prevent exhaustion in the tumor microenvironment (TME), and increase the specificity of the CAR-T cell to various tumor antigens. However, much less effort has been placed on enhancing CAR-T cells' invasion into and migration through the stromal matrix of the TME, where they can elicit tumor-directed cytotoxicity. Here, we engineered CAR-T cells with synthetic cytokine receptors targeting inflammatory cytokines produced by the cells themselves, which increase their speed through collagen I matrices. We show that this enhanced motility is driven by increased CAR-T cell translocation through confined microchannels via cellular deformation, together with elevated migratory speeds in proximity to neighboring cells, suggesting improved responsiveness to local cues. These migration-enhanced CAR-T cells significantly reduce both primary tumor size and distant organ metastasis in triple-negative breast cancer (TNBC) mouse models compared to standard CAR-T cells. These results support molecular design strategies that exploit mechanisms to improve cellular therapies for metastatic solid tumors.
SN - 2692-8205
ER -