Redefining cell therapy: CAR-engineered innate immune cells to conquer solid and hematologic malignancies

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, γδ 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 (γδ 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.