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

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Non-genetically modified adoptive cell therapies (ACTs) are emerging as a safer alternative to genetic engineering for solid tumor immunotherapy.
• CAR-T cell therapy faces challenges in solid tumors, including toxicity, immunosuppressive microenvironments, and resistance.

Purpose of the Study:

• To review the mechanistic basis, clinical progress, and limitations of non-genetically modified ACTs.
• To propose combinatorial strategies to overcome current challenges and enhance clinical applicability.

Main Methods:

• Systematic assessment of tumor-infiltrating lymphocytes (TILs), cytokine-induced killer (CIK) cells, natural killer (NK) cells, and γδ T cells.
• Integration of preclinical and clinical data to identify challenges and solutions.
• Analysis of TME interactions, expansion inefficiencies, and protocol standardization.

Main Results:

• Non-genetically modified ACTs like TILs, CIK, NK, and γδ T cells possess unique advantages against solid tumors.
• Key challenges include inefficient in vitro expansion, lack of standardized protocols, and dynamic TME interactions.
• Combinatorial approaches, patient stratification, and targeted therapies show promise.

Conclusions:

• Non-genetically modified ACTs hold significant therapeutic potential for solid tumors but require further optimization.
• Strategies such as biomarker-guided patient selection, cytokine augmentation, and combination therapies are crucial for clinical success.
• Addressing expansion inefficiencies and TME hurdles is essential to bridge the gap between experimental promise and clinical reality.