The innate regenerome: Harnessing mesenchymal niches and engineered cytotoxic killers for solid tumor immunotherapy

Solid tumors evade adaptive immunity through MHC class I downregulation, stromal barricades, and T-cell exhaustion, rendering conventional immunotherapies ineffective in "cold" lesions. This review introduces the Innate Regenerome, a unified framework harnessing mesenchymal stromal cells (MSCs), CAR-engineered natural killer (CAR-NK) cells, and CAR-macrophages (CAR-M) to simultaneously eliminate malignancy and restore tissue architecture. MSCs serve as switchable niche engineers, delivering logic-gated anti-fibrotic and chemotactic cues. CAR-NK cells provide rapid, non-exhaustible cytotoxicity with favorable safety and metabolic flexibility for hypoxic tumors. CAR-M function as phagocytic engines and antigen-presenting factories, converting engulfed debris into adaptive immunity. We propose a tripartite circuit where MSCs scaffold the niche, CAR-NK cells generate immunogenic stress, and CAR-M complete clearance and cross-presentation. Emerging strategies include EV-mediated coordination, synNotch spatial gating, and in vivo mRNA-LNP programming. Translational priorities comprise humanized MISTRG6 models, organoid-on-chip platforms, and response endpoints beyond RECIST. The Innate Regenerome repositions innate immunity from auxiliary force to central architect of antitumor and regenerative therapy.