Biofactors. 2026 Sep-Oct;52(5):e70150. doi: 10.1002/biof.70150.

ABSTRACT

Gastrointestinal malignancies, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, its efficacy in gastrointestinal solid tumors remains limited by antigen heterogeneity, insufficient trafficking and infiltration, immunosuppressive tumor microenvironments, on-target off-tumor toxicity, and adaptive resistance. In this review, we summarize the current landscape of CAR-T therapy in gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, with a focus on representative target antigens and emerging biomarker strategies. We further discuss two major categories of biomarkers: target antigen-related biomarkers and conventional dynamic biomarkers, including serum tumor markers, cytokine changes, CAR-T expansion kinetics, and antigen-loss monitoring. In addition, we highlight how single-cell ribonucleic acid sequencing and spatial transcriptomics provide complementary insights into cellular states, immune exhaustion, stromal barriers, and spatially restricted immune exclusion. By integrating these multi-omics approaches with biomarker-guided patient stratification and next-generation CAR-T engineering, gastrointestinal solid tumor CAR-T therapy may evolve from empirical optimization toward mechanism-driven and precision-guided clinical translation.

PMID:42717494 | PMC:PMC13558850 | DOI:10.1002/biof.70150

Biofactors. 2026 Sep-Oct;52(5):e70150. doi: 10.1002/biof.70150.

ABSTRACT

Gastrointestinal malignancies, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, its efficacy in gastrointestinal solid tumors remains limited by antigen heterogeneity, insufficient trafficking and infiltration, immunosuppressive tumor microenvironments, on-target off-tumor toxicity, and adaptive resistance. In this review, we summarize the current landscape of CAR-T therapy in gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, with a focus on representative target antigens and emerging biomarker strategies. We further discuss two major categories of biomarkers: target antigen-related biomarkers and conventional dynamic biomarkers, including serum tumor markers, cytokine changes, CAR-T expansion kinetics, and antigen-loss monitoring. In addition, we highlight how single-cell ribonucleic acid sequencing and spatial transcriptomics provide complementary insights into cellular states, immune exhaustion, stromal barriers, and spatially restricted immune exclusion. By integrating these multi-omics approaches with biomarker-guided patient stratification and next-generation CAR-T engineering, gastrointestinal solid tumor CAR-T therapy may evolve from empirical optimization toward mechanism-driven and precision-guided clinical translation.

PMID:42717494 | PMC:PMC13558850 | DOI:10.1002/biof.70150

Biofactors. 2026 Sep-Oct;52(5):e70150. doi: 10.1002/biof.70150.

ABSTRACT

Gastrointestinal malignancies, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, its efficacy in gastrointestinal solid tumors remains limited by antigen heterogeneity, insufficient trafficking and infiltration, immunosuppressive tumor microenvironments, on-target off-tumor toxicity, and adaptive resistance. In this review, we summarize the current landscape of CAR-T therapy in gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, with a focus on representative target antigens and emerging biomarker strategies. We further discuss two major categories of biomarkers: target antigen-related biomarkers and conventional dynamic biomarkers, including serum tumor markers, cytokine changes, CAR-T expansion kinetics, and antigen-loss monitoring. In addition, we highlight how single-cell ribonucleic acid sequencing and spatial transcriptomics provide complementary insights into cellular states, immune exhaustion, stromal barriers, and spatially restricted immune exclusion. By integrating these multi-omics approaches with biomarker-guided patient stratification and next-generation CAR-T engineering, gastrointestinal solid tumor CAR-T therapy may evolve from empirical optimization toward mechanism-driven and precision-guided clinical translation.

PMID:42717494 | PMC:PMC13558850 | DOI:10.1002/biof.70150

EMBO Mol Med. 2026 Mar 30. doi: 10.1038/s44321-026-00410-y. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC, yet reliable predictors of therapeutic response remain unavailable. Using single-cell multi-omics profiling of paired pre- and post-treatment tumor and blood samples, we observed that patients responding to IC exhibited significantly higher baseline levels of peripheral blood monocytes, tumor-infiltrating classical monocytes, and APOBEC3A+ monocytes across both compartments compared with non-responders. These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.

PMID:41912871 | DOI:10.1038/s44321-026-00410-y

EMBO Mol Med. 2026 Mar 30. doi: 10.1038/s44321-026-00410-y. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC, yet reliable predictors of therapeutic response remain unavailable. Using single-cell multi-omics profiling of paired pre- and post-treatment tumor and blood samples, we observed that patients responding to IC exhibited significantly higher baseline levels of peripheral blood monocytes, tumor-infiltrating classical monocytes, and APOBEC3A+ monocytes across both compartments compared with non-responders. These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.

PMID:41912871 | DOI:10.1038/s44321-026-00410-y