CAR-Mast Cell Therapy for Solid Tumor

Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology

First Advisor

Su, Xiaolei

Abstract

While chimeric antigen receptor (CAR)-T cell therapy has revolutionized blood cancer treatment, its efficacy against solid tumors remains limited. Mast cells are tissue-resident granulocytes critical for host defense; however, their role in tumor progression remains unclear. To explore the therapeutic potential of mast cells, we engineered the first CAR-mast cells using an FcεR1γ-based signaling domain. These CAR-mast cells demonstrated antigen-specific activation and gained robust cytotoxicity--absent in native mast cells--to directly kill tumor cells via targeted TNF-α release. Furthermore, CAR-mast cells exhibited both repetitive and bystander killing of cancer targets. In syngeneic mouse models (MC38 colon cancer and EMT6 breast cancer), CAR-mast cells significantly outperformed CAR-T cells in eradicating tumors. This superior efficacy correlated with increased infiltration of NK and NKT cells into the tumors. Importantly, CAR-mast cell administration did not trigger systemic anaphylactic responses. Collectively, these findings establish proof-of-concept for CAR-mast cell therapy as a potent and durable strategy against solid tumors.

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