Cellular immunotherapy in gastrointestinal and liver cancers: mechanisms of resistance and therapeutic opportunities

Gastrointestinal cancers, which include colorectal, esophageal, gastric, and pancreatic cancers and often include cholangiocarcinoma, together with hepatocellular carcinoma, account for a substantial proportion of global cancer incidence and mortality. These malignancies are characterized by complex and highly immunosuppressive tumor microenvironments (TME), which limit the effectiveness of conventional and immune-based therapies. While immune checkpoint inhibitors have shown clinical benefit in selected subsets, particularly in HCC and microsatellite instability-high tumors, most patients fail to achieve durable responses. In parallel, advances in cellular immunotherapy, including CAR-T cells, CAR-NK cells, and other engineered immune effectors, have revolutionized the treatment of hematological malignancies but have demonstrated limited success in solid tumors. Scientific evidence indicates that the intricate interconnection between tumor cells, stromal components, and immune populations critically shapes therapeutic outcomes, underscoring the need for integrated approaches targeting both tumor cells and their microenvironment.Despite significant progress in cancer immunotherapy, gastrointestinal and liver cancers remain largely resistant to current treatment modalities. The main challenge is in the highly immunosuppressive and heterogeneous TME, which actively impairs immune cell infiltration, persistence, and cytotoxic function. Physical barriers such as dense stroma (desmoplasia), abnormal vasculature, and hypoxia, together with immunoregulatory networks driven by an enriched population of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, contribute to therapeutic failure. Although cellular immunotherapies, including CAR-T, CAR-NK, γδ T cells, and tumor-infiltrating lymphocytes, hold great promise, their efficacy in these tumors is still limited by these microenvironmental constraints.Recent advances in multiOmics profile, spatial transcriptomics, organoid-based systems, and improved in vivo models have provided new insights into TME complexity and immune-tumor interactions. Additionally, innovative strategies such as CAR constructs, combinatorial therapies with immune checkpoint inhibitors, stromal reprogramming, and metabolic modulation are emerging to enhance therapeutic efficacy. This research topic aims to address these challenges by fostering a comprehensive understanding of the cellular and molecular mechanisms underlying resistance and by identifying novel strategies to improve the clinical translation of cellular immunotherapies.This Topic seeks contributions that explore the interplay between cellular immunotherapy and the tumor microenvironment in gastrointestinal and liver cancers. We welcome both fundamental and translational studies that provide mechanistic insights and therapeutic innovation.Themes of interest include:• Cellular immunotherapies: CAR-T, CAR-NK, γδ T cells, TILs, and emerging engineered immune cells • Tumor microenvironment composition and function (CAF, TAMs, MDSCs, Tregs, endothelial cells) • Mechanisms of immune cell trafficking, infiltration, persistence, and exhaustion • Stromal and vascular barriers to immunotherapy • Metabolic regulation and immune evasion • Preclinical models (in vitro systems, spheroids, organoids and in vivo models) • Early-phase clinical trials and translational studies • Combination therapies (checkpoint inhibitors, bispecific antibodies, stromal targeting, metabolic interventions and nanoantibodies)Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Topic editors: Javier Martinez-Useros, Jesus Garcia-Foncillas, Esteban Veiga, Silvia Martin Lluesma Source: https://www.frontiersin.org/research-topics/81928/cellular-immunotherapy-in-gastrointestinal-and-liver-cancers-mechanisms-of-resistance-and-therapeutic-opportunities