고형암 극복을 위한 차세대 CAR-T 세포 치료제 개발 전략

초록

Conventional cancer treatments—including surgery, chemotherapy, radiotherapy, and immune checkpoint inhibitors—have improved outcomes but remain limited by metastasis, recurrence, drug resistance, and off-target toxicity. CAR-T therapy has achieved durable remissions in hematologic malignancies, yet its efficacy in solid tumors is constrained by an immunosuppressive tumor microenvironment (TME), antigen heterogeneity and loss, poor tumor penetration, limited in vivo persistence, and safety concerns. This review summarizes four strategic directions to extend CAR-T performance in solid tumors. First, CAR engineering is advanced to broaden antigen recognition and enhance function, including signaling rewiring, fourth-generation TRUCK designs secreting immunomodulatory cytokines (e.g., IL-12, IL-18), and dual-antigen TanCAR architectures. Second, approaches to overcome TME-mediated suppression and physical barriers aim to improve migration, infiltration, and persistence, such as TGF-β resistance, checkpoint or inhibitory receptor modulation, chemokine receptor expression (e.g., CXCR2, CCR2), and extracellular matrix–degrading enzymes. Third, antigen escape is addressed by prioritizing relatively selective targets (e.g., GD2, HER2) and dual-targeting platforms. Fourth, combination strategies with oncolytic viruses may potentiate CAR-T activity by promoting antigen exposure and TME reprogramming. Together, these advances support the feasibility of precision, patient-tailored CAR-T immunotherapy for refractory solid tumors.

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