重新定义细胞治疗：CAR 工程化固有免疫细胞攻克实体瘤和血液系统恶性肿瘤

Chimeric antigen receptor (CAR) technology has revolutionized cancer therapy, yet its full potential remains untapped within the innate immune system. Beyond CAR-T cells, a growing cadre of MHC-independent effectors, including NK cells, macrophages, T cells and the emerging innate-like T cells such as invariant NKT (iNKT) and mucosal-associated invariant T (MAIT) cells, offer complementary mechanisms for tumor recognition and elimination.

These platforms combine facile, off-the-shelf manufacture from healthy donors with low graft-versus-host disease risk and a reduced propensity for severe cytokine release syndromes.

Mechanistically, they span missing-self and antibody-dependent cytotoxicity (NK), phagocytosis and cross-presentation (macrophages), stress-ligand recognition ( T cells), and rapid, tissue-tropic, TCR-mediated responses to conserved lipid and metabolite antigens (iNKT via CD1d; MAIT via MR1). CAR engineering of these cells leverages their innate rapidity, innate/adaptive cross-talk, and distinctive homing to confront heterogeneous and immune-evasive tumors.

Here, we synthesize recent advances in cell design, dual/split CARs, switchable control systems, armored payloads and synthetic-biology circuits, and evaluate translational progress, manufacturing bottlenecks, and regulatory considerations.

We argue that integrating innate and innate-like programs with precision CAR architectures will yield a new generation of universal, resilient cellular therapeutics with broadened antigen reach, improved safety profiles, and enhanced capacity to overcome the suppressive tumor microenvironment.