Non-Genetically Modified Adoptive Cell Therapies for Solid Tumors: Current Landscape and Future Challenges

Non-genetically modified adoptive cell therapies (ACTs) represent a rapidly advancing frontier in solid tumor immunotherapy, offering a safe and adaptable alternative to genetically engineered approaches by capitalizing on the intrinsic plasticity of immune cells. Genetic engineering strategies, including CAR-T cells, encounter significant obstacles in solid tumors, including on-target off-tumor toxicity, an immunosuppressive tumor microenvironment, and drug resistance. Although non-genetically modified ACTs-including tumor-infiltrating lymphocytes (TILs), cytokine-induced killer (CIK) cells, natural killer (NK) cells, and γδ T cells-offer unique advantages, their clinical application remains underexplored. This review consolidates the mechanistic basis, clinical progress, and limitations of non-genetically modified ACTs, proposing a paradigm shift toward combinatorial strategies. We systematically assessed how TILs overcome tumor microenvironment (TME) inhibition through lymphodepletion and cytokine assistance, compared the histocompatibility complex-unrestricted cytotoxicity of CIK cells with their functional diversity, and emphasized the innate flexibility of NK/γδ T cells against antigen-loss variants. By integrating preclinical and clinical data, we identify critical challenges: in vitro expansion inefficiency, absence of standardized protocols, and dynamic TME interactions. Furthermore, we advocated patient stratification by biomarkers, the addition of optimized cytokines, and rational combinations with checkpoint inhibitors or metabolic modulators to enhance efficacy. This review outlines the current landscape and proposes actionable solutions to reconcile the disparity between experimental potential and clinical applicability in non-genetically modified ACT.