From glycoprotein biology to immunotherapy: the roadmap for MUC1-directed CAR T cells

Chimeric Antigen Receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, yet its translation to solid tumors remains hindered by antigen heterogeneity, immunosuppressive microenvironments, and safety concerns. MUC1, a transmembrane glycoprotein aberrantly expressed and glycosylated in diverse carcinomas, represents a compelling target due to epitopes generally restricted in normal tissues. This review synthesizes current knowledge of MUC1 biology, including its glycoforms and splice variants, and their roles in oncogenesis, immune evasion, and therapy resistance. We highlight advances in MUC1‑directed CAR design, encompassing optimized targeting domains, hinge flexibility, and co‑stimulatory modules, alongside combinatorial strategies such as dual CAR constructs, switch receptors, and cytokine engineering. Collectively, these innovations underscore both the promise and complexity of MUC1‑targeting CAR T cells. By integrating structural, functional, and translational insights, this review positions MUC1 as a paradigm for next‑generation CAR therapies against solid tumors, while emphasizing the need for precision design and rigorous clinical validation.