Tumor Microenvironment and Cancer Cell Biology in Gastrointestinal and Hepatopancreatobiliary Cancers: Mechanisms, Cell States, and Therapeutic Vulnerabilities

Gastrointestinal (GI) and hepatopancreatobiliary (HPB) cancers—including pancreatic and liver cancers—remain leading causes of cancer mortality worldwide due to late diagnosis, aggressive tumor biology, and limited durable therapeutic responses. A defining feature of these malignancies is a complex and often immunosuppressive tumor microenvironment (TME), where dynamic interactions between cancer cells, immune infiltrates (e.g., macrophages and T cells), and stromal components (e.g., cancer-associated fibroblasts and extracellular matrix) shape tumor cell states, promote progression and metastasis, and drive resistance to chemotherapy, targeted therapy, and immunotherapy.Recent advances in single-cell and spatial multi-omics, proteogenomics, digital pathology, and translational model systems now enable a deeper, biology-first dissection of tumor cell programs and their functional crosstalk with the TME in clinically relevant contexts. This Research Topic will compile original research, reviews, and perspectives that elucidate mechanisms by which cancer cell states and TME interactions regulate pathogenesis, therapeutic response, and treatment resistance across GI and HPB malignancies (e.g., pancreatic ductal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, gastric cancer, and colorectal cancer).We particularly welcome submissions that provide mechanistic insight and/or functional validation of tumor-cell or TME programs (in vitro, ex vivo, and/or in vivo), and that identify therapeutic vulnerabilities or biologically grounded biomarkers linked to disease behavior.Please note: studies that are purely observational, limited to clinical correlations or prognostic modeling without biological rationale or validation, fall outside the scope of this Research Topic.Submissions may include, but are not limited to:Mechanistic studies of tumor cell–immune–stroma interactions that regulate invasion, metastasis, immune evasion, and therapy resistance.Functional dissection of cancer cell states (e.g., stress responses, EMT-like programs, stemness, metabolic rewiring) and how the TME shapes state transitions and plasticity.Studies leveraging single-cell/spatial multi-omics, proteogenomics, and advanced imaging/digital pathology to resolve heterogeneity, ideally paired with orthogonal validation and/or perturbation experiments.Discovery and validation of biologically grounded biomarkers (omics, liquid biopsy, imaging, or tissue-based markers) that reflect underlying mechanisms and predict therapy response or resistance.Translational model systems (patient-derived organoids, xenografts, ex vivo cultures, co-culture systems) that link TME features to tumor cell phenotypes and therapeutic sensitivities.Novel therapeutic strategies and combinations targeting tumor cell pathways and/or specific TME components, supported by mechanistic rationale and preclinical evidence.Reviews and perspectives synthesizing emerging concepts, technical challenges, and future directions in GI and HPB cancer cell biology within the TME. Topic editors: Yiping Zou, Libo Wang Source: https://www.frontiersin.org/research-topics/77077/tumor-microenvironment-and-cancer-cell-biology-in-gastrointestinal-and-hepatopancreatobiliary-cancers-mechanisms-cell-states-and-therapeutic-vulnerabilities