Emerging Horizons in Cell-Based Immunotherapies for Cancers

Adoptive cell therapies (ACT) have become a transformative force in cancer immunology, offering powerful platforms for targeting both hematological and solid malignancies. Recent progress in cellular engineering and manufacturing has accelerated the development of diverse ACT modalities, including chimeric antigen receptor (CAR) T and natural killer (NK) cells, dual-targeting strategies, and innovative designs aimed at overcoming the specific challenges of non-hematological cancers such as gliomas and refractory solid tumors. Despite these advances, ACT still faces key obstacles, including the hostile tumor microenvironment, limited trafficking and persistence of effector cells, and mechanisms underlying therapy-associated toxicities. These challenges underscore the need for continued research into next-generation cellular products, molecular engineering strategies, and rational combinatorial approaches.

A rapidly expanding body of preclinical and translational studies highlights major developments in the field: application of CRISPR and other gene-editing tools to enhance cellular fitness and persistence; engineering of innate-like, synthetic, or exhaustion-resistant T cells; and reprogramming of tumor-associated myeloid cells to reshape local immune responses. In parallel, advances in high-throughput genetic manipulation, artificial intelligence–driven target discovery, systems immunology, and scalable bioprocessing are redefining what is achievable with cell-based immunotherapies. However, substantial knowledge gaps remain, particularly regarding the determinants of durable activity in solid tumors, the identification and validation of robust biomarkers for patient or disease stratification, the mechanistic basis of immune-related toxicities, and the extension of ACT concepts beyond oncology to autoimmune and infectious disease settings. Ongoing discussion in the field also centers on the relative merits of autologous versus allogeneic platforms, the integration of immune checkpoint modulation, and the rational design of combination strategies to enhance cellular function and persistence.

This Research Topic aims to showcase the latest innovations, emerging concepts, and translational advances in ACT, with a focus on mechanistic, technological, and preclinical work rather than clinical trial outcomes. We seek contributions that clarify fundamental and translational questions surrounding cellular engineering, target selection, immune evasion, toxicity mechanisms, and rational combination strategies. We particularly welcome research that: (i) pioneers improved persistence, fitness, and function of therapeutic cells, (ii) elucidates interactions between engineered cells, the tumor and tissue microenvironment, and other immune compartments, and (iii) explores scalable, robust solutions to broaden the applicability and accessibility of ACT across cancer and non-cancer indications.

To gather further insights into the emerging landscape and technical boundaries of ACT, we welcome articles addressing, but not limited to, the following themes:

- Genetic engineering of T, NK, and innate-like cells for enhanced target recognition, persistence, and resistance to exhaustion

- Combination strategies involving checkpoint modulation, cytokines, costimulatory agents, or other immunomodulators at the mechanistic or preclinical level

- Approaches to overcome barriers in the solid tumor microenvironment, including improved homing, infiltration, and survival of transferred cells

- Advanced manufacturing, bioprocess development, and scalability for high-quality adoptive cell products

- High-throughput target discovery and design using artificial intelligence, multi-omics, and large-scale datasets

- Novel biomarkers and correlative strategies for characterizing response, resistance, and toxicity to ACT in translational and preclinical settings

- Mechanistic studies and innovative designs to minimize toxicities (e.g., cytokine release syndrome–like phenomena, on-target/off-tumor effects) while preserving antitumor function

- Adaptation and application of ACT principles to autoimmune and infectious diseases, including target and platform design

- Comparative and conceptual analyses of autologous versus allogeneic ACT platforms, including immunobiological, manufacturing, and translational considerations