Front Immunol. 2026 Aug 20;17:1919864. doi: 10.3389/fimmu.2026.1919864. eCollection 2026.

ABSTRACT

Cholangiocarcinoma is an aggressive biliary tract malignancy in which metastatic relapse and primary or acquired resistance to immunotherapy remain major causes of mortality. Although immune checkpoint inhibitors have improved first-line treatment for advanced biliary tract cancer, most patients do not achieve durable benefit, indicating that immune failure is not explained by a single checkpoint pathway. In this Review, we propose a spatial immune-regulatory continuum for cholangiocarcinoma dissemination. Most direct single-cell and spatial evidence currently derives from intrahepatic cholangiocarcinoma, and its applicability to perihilar and distal disease remains to be established. This continuum begins in the tumor core and invasive front, where malignant cells, cancer-associated fibroblasts, tumor-associated macrophages, endothelial and lymphatic cells, regulatory T cells, immature neutrophils and excluded or dysfunctional cytotoxic T cells form a pro-invasive ecosystem. It then extends through extracellular vesicles, soluble mediators and lymphovascular routes that may educate organotropic pre-metastatic niches. Finally, lymph node, lung, liver, peritoneal and bone microenvironments provide organ-specific extracellular matrix, myeloid and stromal programs that enable immune evasion and metastatic colonization. By integrating clinical evidence, multi-omics studies, single-cell and spatial transcriptomics, extracellular vesicle biology, pre-metastatic niche concepts and emerging therapeutic strategies, we argue that cholangiocarcinoma metastasis should be targeted before overt dissemination whenever possible. In this Review, "metastasis-intercepting immunotherapy" is used as an author-defined conceptual framework for strategies intended to prevent or disrupt the immune-stromal conditions that enable dissemination and colonization, rather than merely shrink established metastatic lesions. Metastasis-intercepting immunotherapy will likely require rational combinations that reprogram the invasive front, restore dendritic-cell-mediated antigen presentation, block tumor-stroma-myeloid circuits, disrupt EV-mediated communication that may contribute to niche formation and select patients using spatial biomarkers rather than bulk immune markers alone.

PMID:42694469 | PMC:PMC13539491 | DOI:10.3389/fimmu.2026.1919864

Front Physiol. 2026 Aug 20;17:1930628. doi: 10.3389/fphys.2026.1930628. eCollection 2026.

ABSTRACT

BACKGROUND: Gastrointestinal motility disturbances rank among the most frequently reported medical complications of spaceflight. Astronauts experience delayed gastric emptying, erratic small intestinal transit and reduced colonic propulsion. The underlying mechanisms are multifactorial. Microgravity alters intra-abdominal physical mechanics, disrupts autonomic and enteric neural circuits, shifts gastrointestinal hormone secretion profiles, inflicts oxidative stress upon effector cells, and perturbs gut microbial communities. Cross-model comparisons reveal substantial disagreement, suggesting that no single ground-based analog fully captures the pathophysiology of orbital flight.

AIM: To critically review how weightlessness affects gastric emptying, small intestinal transit and colonic motility; to critically evaluate contradictory findings across simulation platforms; and to delineate the neural, humoral, cellular and microbiological mechanisms involved.

METHODS: We searched PubMed, Web of Science and the NASA Technical Reports Server for articles published between January 1990 and June 2026 (last search 30 June 2026). Search terms included: "microgravity", "weightlessness", "spaceflight", "gastrointestinal motility", "gastric emptying", "intestinal transit", "gut microbiome", "interstitial cells of Cajal" and "oxidative stress". Studies using head-down bed rest, hindlimb unloading, clinorotation, parabolic flight and actual spaceflight were included. The review follows a critical narrative design; the full search strategy and the framework used to appraise the evidence are described in Section 1.1.

RESULTS: Altered-gravity studies suggest that gastrointestinal dysmotility may involve neurohumoral dysregulation, oxidative injury to interstitial cells of Cajal and smooth muscle, barrier dysfunction and altered enteric signaling; however, most mechanistic evidence derives from simulated models and has not been directly validated during human spaceflight. Direct human motility measurements remain sparse, and the evidence comprises a mixture of direct observations, model-dependent inferences and testable hypotheses. Cross-study agreement is poor: some head-down bed rest trials report accelerated small-bowel transit, whereas tail-suspension models and limited flight observations suggest motor suppression. These divergences may reflect model-specific confounding rather than a uniform effect of microgravity.

CONCLUSION: Current ground-based models each capture only partial aspects of orbital GI pathophysiology. Future work should combine multi-omics profiling with next-generation simulation platforms to develop evidence-based countermeasures for long-duration missions.

PMID:42694486 | PMC:PMC13539599 | DOI:10.3389/fphys.2026.1930628