The clinical backdrop makes the advance urgent. Gastric cancer remains one of the world’s deadliest malignancies, characterized by molecular heterogeneity, a high propensity for metastatic spread, and frequent therapeutic resistance. Immune checkpoint blockade, particularly antibodies against the PD-1/PD-L1 axis, has transformed outcomes in several tumor types, yet in gastric cancer the response rates stubbornly remain below 30 percent, with a substantial fraction of patients showing intrinsic resistance from the very first dose. The researchers turned to cancer genetics for an explanation. A significant subset of gastric cancers, especially those defined by chromosomal instability, carry two simultaneous alterations: loss of the tumor suppressor TP53 and hyperactivation of YAP, the transcriptional co-activator that serves as the main effector of the Hippo signaling pathway. YAP1 is amplified in roughly 18 percent of human gastric cancers, and the combination of YAP activation with p53 loss correlates clinically with aggressive, refractory disease. Whether this genetic pairing was a mere correlation or a true causal driver of immunotherapy resistance was the central question the study set out to answer.

To probe that question, the investigators engineered a sophisticated mouse model they call AYP. These animals carry a conditional, constitutively active YAP1 mutant, designated Yap1-6A, in which six phosphorylation sites were mutated so the protein resists degradation, together with floxed Tp53 alleles. Both alterations were activated specifically in the Atp4b-expressing parietal cell lineage of the stomach, which encompasses parietal cell progenitors, pre-parietal cells, and mature acid-producing cells. After tamoxifen induction, the mice developed invasive gastric adenocarcinoma within two to three months, with a median survival of 131 days. Crucially, the model demonstrated biological synergy rather than mere additivity: mice with YAP activation alone or p53 loss alone failed to develop gastric cancer even ten months after induction, while the double-hit configuration produced fully penetrant, aggressive malignancy. Histopathological examination revealed the full spectrum of human disease, including well-differentiated intestinal-type tumors, poorly differentiated signet-ring cell carcinomas of the diffuse type, and mixed forms, all accompanied by dense immune infiltration.

The metastatic behavior of the model proved equally faithful to the human condition. By three to four months after induction, the majority of AYP mice had disseminated disease involving the gastric lymph node, diaphragm, liver, pancreas, mediastinal lymph node, and lung, with metastatic incidence rates recorded for each organ across the cohort. Fluorescent labeling confirmed that the metastatic lesions originated from the Atp4b-lineage tumor cells. When the researchers treated these mice with anti-PD-1 antibodies for three weeks, the results were sobering but clinically familiar: stomach weights were unchanged, metastatic incidence and morphology were unaltered, and histopathology confirmed no therapeutic response. Immune profiling showed only a modest reduction in neutrophils, regulatory T cells, and group 3 innate lymphoid cells. In other words, the AYP tumors were intrinsically resistant to PD-1 blockade despite being what immunologists would call hot tumors, densely infiltrated with immune cells that should, in principle, be attackable.

To find the mechanism, the team performed single-cell RNA sequencing on nearly 50,000 high-quality cells harvested from the stomach, gastric lymph node, and visible liver and lung metastases of AYP mice and matched wild-type controls. The analysis identified three distinct tumor cell clusters, and gene set variation analysis revealed strong enrichment of Hippo signaling, YAP/TAZ target gene signatures, epithelial-mesenchymal transition features, and immunosuppression programs. When the researchers compared the mouse tumor transcriptomes with a single-cell dataset from 26 gastric cancer patients, the AYP tumor cells correlated closely with human poorly differentiated gastric adenocarcinoma, including signet-ring cell carcinoma, with high correlation coefficients for signature genes such as OLFM4, PLA2G2A, and ENO1. A dominant feature of the microenvironment, at both primary and metastatic sites, was a pronounced infiltration of neutrophils displaying characteristics of polymorphonuclear myeloid-derived suppressor cells, key systemic mediators of immunosuppression that are clinically associated with poor immunotherapy responses. Depleting neutrophils substantially inhibited tumor development and metastasis, establishing these cells as essential players rather than bystanders.

The search for the molecular bridge between YAP and the suppressive microenvironment converged on BST2, or bone marrow stromal cell antigen 2. Integrated analysis of tumor cell signature genes and genes downregulated after YAP1 knockout identified BST2 as a top candidate. Immunofluorescence confirmed that BST2 was co-expressed with the tumor marker KRT7 specifically within tumor tissue and was undetectable in normal gastric epithelium. Clinically, the pattern was striking: both BST2 and YAP1 transcription were markedly higher in gastric cancer patients whose disease progressed on anti-PD-1 therapy than in those achieving complete or partial responses, mirroring established immunosuppressive markers such as NR4A1 and CD55. Mechanistically, the team showed that deleting YAP1 with CRISPR/Cas9 significantly reduced both BST2 mRNA and surface protein levels, and CUT&RUN assays demonstrated direct binding of the YAP1-TEAD4 transcriptional complex to the Bst2 promoter, formally establishing BST2 as a direct YAP target gene.

Functional experiments then revealed BST2 as a genuine immune checkpoint operating on innate immune cells. Deleting BST2 from AYP tumor cells had only a marginal effect on proliferation in a dish but significantly impaired tumor formation and growth in living mice, accompanied by reduced numbers of tumor-infiltrating neutrophils and lower PD-L1 expression on those cells, decreased exhaustion of natural killer and CD4 T cells, and increased production of the cytotoxic enzyme Granzyme B. Ligand-receptor interaction analysis pointed to BST2 engaging a receptor called PIRA2, the murine ortholog of human leukocyte immunoglobulin-like receptors, which is highly expressed on neutrophils. Co-immunoprecipitation and protein truncation experiments mapped the physical interface: the coiled-coil domain of BST2 directly binds the Ig-like domain of PIRA2 through two distinct contact surfaces. Co-culture assays confirmed that AYP tumor cells drive bone marrow cells toward an immunosuppressive SiglecF-positive, PD-L1-positive neutrophil phenotype, an effect abolished either by BST2 knockout or by a BST2-blocking antibody.

The liver emerged as a particularly instructive battleground. Kupffer cells, the resident macrophages of the liver, also express high levels of PIRA2, and transcriptional profiling showed that AYP mice accumulated immunosuppressive Kupffer cell subsets at the expense of immunostimulatory ones. In co-culture, AYP tumor cells expanded the pool of CD11b-high Kupffer cells and upregulated the suppressive markers Arg1 and PD-L1, effects again dependent on BST2. In a liver metastasis model based on splenic injection of tumor cells, BST2 deficiency significantly prolonged host survival, reduced metastatic tumor burden, and boosted Granzyme B production by liver CD8 T cells, indicating reinvigorated anti-tumor immunity. The therapeutic culmination came in the spontaneous AYP model itself: combining anti-BST2 with anti-PD-1 antibodies reduced stomach weights by nearly 30 percent compared with anti-PD-1 alone, restored glandular tissue architecture, and, most strikingly, completely eradicated visible liver metastases in all treated animals while suppressing lymph node spread beyond what either agent achieved alone.

The implications reach beyond gastric cancer. BST2 was upregulated in tumors from resistant patients across multiple cancer types, suggesting it may function as a pan-tumor marker of anti-PD-1 failure, and its known role in suppressing plasmacytoid dendritic cells offers a plausible explanation for how anti-BST2 therapy also curbed lymph node metastases. The study also raises tantalizing questions about the microbial dimension, since bacteria such as Helicobacter pylori and Streptococcus anginosus can activate YAP signaling in gastric epithelium, potentially sustaining the BST2-driven resistance program. Significant work remains before patients benefit: the downstream signaling events of BST2-PIRA2 engagement are not fully mapped, structural studies of the interaction are needed to design high-affinity blockers, and humanized anti-BST2 antibodies must now prove themselves in patient-derived models. Still, for the large population of patients whose hot, immune-infiltrated gastric tumors inexplicably shrug off PD-1 blockade, the identification of a druggable YAP-BST2 axis offers something they have not had before: a mechanistic explanation and a concrete combination strategy to test in the clinic.

Subject of Research: YAP-BST2-mediated intrinsic resistance to anti-PD-1 immunotherapy in metastatic gastric cancer

Article Title: Targeting the YAP‐BST2 Axis Overcomes Intrinsic Anti‐PD‐1 Resistance in Metastatic Gastric Cancer

Article References: Zhang, W., Wang, S., Wang, M., Yu, R., Yue, J., Shao, L., Zhang, H., Zhu, M., Tian, L., Cheng, S., Qin, W., Tang, Y., Han, Y., Wang, W., An, L., Meng, Y., Jiao, S., & Zhou, Z. (2026). Targeting the YAP‐BST2 Axis Overcomes Intrinsic Anti‐PD‐1 Resistance in Metastatic Gastric Cancer. Advanced Science, Article e77708. https://doi.org/10.1002/advs.77708

Image Credits: AI Generated

DOI: 10.1002/advs.77708

Keywords: gastric cancer, immunotherapy resistance, YAP, TP53, BST2, PD-1, neutrophils, Kupffer cells, PIRA2, Hippo pathway, mouse model, liver metastasis

SALI is defined as an acute, secondary hepatic dysfunction that arises during sepsis and is observed in roughly 34 to 46 percent of patients. At the bedside it announces itself through abnormalities in standard liver tests, which can follow hepatocellular, cholestatic, or mixed patterns and range from modest enzyme elevations to profound liver failure. Crucially, the authors insist that SALI be treated as an operational clinical syndrome rather than the signature of a single underlying mechanism. Abnormal liver biochemistry in a septic patient may reflect inflammatory injury, cholestasis, hypoxic hepatitis caused by insufficient oxygen delivery, right-sided cardiac congestion, drug toxicity, or pre-existing conditions such as metabolic dysfunction-associated steatotic liver disease and occult fibrosis. The question, they argue, is not whether SALI has uniform biology, because it does not, but whether routinely available data can flag the patients most likely to deteriorate.

On the mechanistic side, one of the most striking recent findings concerns the gut. In a mouse model of sepsis, Murao and colleagues identified a pathway in which gut-primed neutrophils drive hepatic injury. Gut intraepithelial lymphocytes interact with neutrophils through the molecule CD112, facilitating the formation of neutrophil extracellular traps, the web-like DNA structures that neutrophils eject to ensnare pathogens. These primed neutrophils migrate through the portal vein into the liver, where they release their traps and activate Kupffer cells, the liver’s resident macrophages, triggering the secretion of interleukin-6 and tumor necrosis factor-alpha. Notably, portal vein neutrophils from septic mice produced significantly more neutrophil extracellular traps and induced greater Kupffer cell activation than systemic neutrophils, an effect that disappeared entirely in mice lacking PAD4, the enzyme essential for trap formation. The implication is provocative: the gut does not merely spill inflammatory mediators into the portal circulation, it actively educates immune cells that then inflict damage on distant organs.

Although the authors caution that translation to human disease requires care, the concept has clear clinical resonance. The liver receives most of its blood supply from the portal circulation and is therefore continuously bathed in gut-derived inflammatory signals. During sepsis, disruption of the intestinal barrier allows bacterial translocation and the spillover of pathogen-associated molecular patterns, which activate hepatic Toll-like receptors. Supporting this mechanistic bridge, human data from Czaikoski and colleagues have shown that neutrophil extracellular traps accumulate in organ tissue during experimental and clinical sepsis and correlate with damage. Together, these findings nominate trap formation and downstream Kupffer cell activation as candidate precision-medicine targets in SALI.

A second biological pillar concerns the loss of hepatic immune tolerance. In health, the liver is a strikingly tolerant organ, and Kupffer cells orchestrate that tolerance through antigen clearance and the induction of regulatory T cells. Recent work shows that during hepatic inflammation this tolerogenic phenotype collapses: Kupffer cells lose their signature tolerance markers, and antigen presentation shifts to infiltrating monocyte-derived macrophages. Activated Kupffer cells then recruit further immune cells to the liver, amplifying injury. Evidence from viral hepatitis research suggests that the transition from tolerance to inflammation involves dysregulation of inhibitory pathways, such as the Toll-like receptor pathway inhibitor SHIP, that normally restrain receptor signaling and keep Kupffer cells quiescent. Hepatic stellate cells, likewise, depend on inhibitory signals to remain dormant; when stimulated by microbial products or damage-associated molecular patterns, they produce extracellular matrix proteins and profibrogenic cytokines, and their contractile activation can raise sinusoidal resistance and portal pressure. Toll-like receptor 4-dependent crosstalk between Kupffer cells and stellate cells converts inflammatory signals into profibrogenic activation.

Within sepsis specifically, the inflammatory polarization of Kupffer cells toward the M1 phenotype has emerged as a hallmark of SALI. Extracellular cold-inducible RNA-binding protein, a damage-associated molecular pattern released during stress, promotes this M1 polarization through Toll-like receptor 4 signaling, driving overproduction of inflammatory cytokines. In mouse sepsis models the ratio of M1 to M2 Kupffer cells rises sharply, indicating a decisive shift toward proinflammatory function, and this polarization is not merely a byproduct of inflammation but an active driver of hepatocyte injury through reactive oxygen species, cytokines, and the recruitment of more neutrophils. In parallel, regulated forms of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, appear to contribute to hepatocyte dysfunction. These converging mechanisms point toward the restoration of hepatic immune tolerance as a promising future therapeutic strategy, though no SALI-targeted therapy has yet been established.

It is on the clinical side that the commentary delivers its most immediately practical message. In a retrospective cohort study spanning two large intensive care cohorts, Palmowski and colleagues examined how well routine biomarkers could stratify mortality risk among patients meeting operational criteria for SALI, defined as sepsis-associated liver-test abnormalities within seven days of sepsis onset, excluding pre-existing chronic liver disease. The criteria included alanine aminotransferase at five or more times the upper limit of normal, alkaline phosphatase at twice the upper limit, or elevated bilirubin combined with enzyme elevations. Their central finding was that the De Ritis ratio, the simple ratio of aspartate to alanine aminotransferase, outperformed both the conventional R-factor and alanine aminotransferase alone in predicting thirty-day mortality. A ratio of one or below indicated low risk, values between one and two indicated intermediate risk, and values of two or above flagged the highest risk, a pattern consistent across infection sources and admission types.

The authors of the commentary are careful to frame these strata correctly. The De Ritis ratio is not a liver-specific diagnostic marker or a mechanistic endotype, and elevated aspartate aminotransferase can also signal hypoxic hepatitis, shock, right-sided congestion, systemic inflammation, chronic kidney disease, alcohol-related injury, or cardiometabolic comorbidity. Its pragmatic value lies in risk enrichment among patients who already meet operational SALI criteria, complementing rather than replacing SOFA-bilirubin scoring. Interpreted alongside the SOFA score, lactate, hemodynamic status, cardiac context, and comorbidities, a rising ratio should trigger a structured reassessment: is infection control optimized, are hemodynamics adequate, is the lactate trajectory improving, is there occult congestion or biliary obstruction, are hepatotoxic drugs on board, and does the patient carry underlying fibrosis risk? In this framework, routine liver tests define the dominant biochemical injury pattern, whether hepatocellular, cholestatic, or mixed, and link prediction to the prevention of further hepatic and systemic deterioration and of iatrogenic harm.

The translational pathway forward, the authors suggest, will require prospective studies testing whether serial liver tests, the De Ritis ratio, SOFA scores, lactate, hemodynamic data, and immune readouts such as monocyte HLA-DR expression or ex vivo monocyte cytokine responses can identify reproducible SALI trajectories and clinically actionable phenotypes. Preclinical work has already nominated an unusually rich set of therapeutic targets, including neutrophil extracellular trap formation, Kupffer cell polarization, inflammasome activation, ferroptosis, necroptosis, and the restoration of hepatic immune tolerance. Until such approaches are validated, however, current clinical utility remains deliberately pragmatic: recognize SALI early, classify the dominant biochemical pattern, stratify mortality risk with the De Ritis ratio, hunt actively for reversible contributors, and intensify surveillance in high-risk patients.

For the authors, the larger significance of this work lies in adding an organ-specific decision layer to the 2026 Surviving Sepsis Campaign framework. New-onset liver-test abnormalities in septic adults, they argue, should no longer be treated as incidental laboratory noise. When detected, the humble ratio of two transaminases, a calculation older than modern critical care and available in every hospital on earth, may identify the patients who need intensified monitoring and protection from modifiable second hits, while the expanding immunobiology of the gut-liver axis steadily maps the routes toward genuine precision medicine for a complication that affects as many as one in two patients with sepsis.

Subject of Research: Sepsis-associated liver injury: immunobiology and bedside risk stratification with routine liver tests

Article Title: Sepsis-associated liver injury: from liver-test risk signals to immunobiology-guided precision medicine

Article References: Katsounas, A., Tsochatzis, E., & Rello, J. (2026). Sepsis-associated liver injury: from liver-test risk signals to immunobiology-guided precision medicine. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08593-1

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08593-1

Keywords: sepsis-associated liver injury, De Ritis ratio, Kupffer cells, neutrophil extracellular traps, gut-liver crosstalk, hepatic immune tolerance, risk stratification, intensive care, Toll-like receptors, precision medicine, Sepsis-associated, liver

Kupffer cells have long been viewed primarily as scavengers, clearing debris and worn-out blood cells from the hepatic circulation. The new work, led by Zhuoyu Jia, Xinqiang Li, and Jinzhen Cai of Qingdao University and collaborators, demonstrates that they are far more sophisticated. Using single-cell RNA sequencing of liver graft biopsies and peripheral blood from transplant patients, the team mapped the full diversity of myeloid cells within the graft and isolated a cluster defined by exceptionally high APOE expression alongside canonical Kupffer cell markers such as CD5L, VSIG4, and MARCO. Functional enrichment analysis showed that this APOE-positive subset was strongly enriched in pathways governing receptor-mediated endocytosis, antigen processing and presentation, and efferocytosis, the engulfment of dying cells, pointing to a cell primed for both scavenging and immune regulation.

Computational modeling of intercellular communication using the CellChat algorithm revealed that these APOE-positive Kupffer cells behave as major signal senders within the graft, engaging T cells through a battery of co-stimulatory and co-inhibitory ligand-receptor pairs. Among the most prominent were CD86 engaging CTLA4 and CD28, LGALS9 binding the inhibitory receptor TIM-3, and NECTIN2 pairing with TIGIT. The strength and pattern of these interactions differed dramatically between patients whose grafts were tolerated and those experiencing rejection, suggesting that the APOE-positive macrophages help determine whether the local immune response escalates or winds down. Multiplex immunohistochemistry of patient biopsies confirmed that the proportions of these cells shift measurably as rejection develops.

To establish causality rather than mere correlation, the researchers built a technically demanding murine model of orthotopic liver transplantation, transplanting livers from C57BL/6 donors into C3H/He recipients and tracking the immune environment across four post-operative weeks. Histology and Banff rejection scoring documented the expected trajectory: severe acute rejection at one week, followed by spontaneous resolution and immune tolerance by week four. Flow cytometry with rigorous fluorescence-minus-one controls then revealed a striking biphasic dynamic. During acute rejection, the proportion of APOE-expressing Kupffer cells in the graft plummeted, likely reflecting ischemia-reperfusion injury and cellular death, while macrophages surged systemically across the spleen, blood, lymph nodes, and bone marrow.

As tolerance took hold, the picture reversed. Systemic myeloid expansion contracted, but the fraction of APOE-positive Kupffer cells within the graft climbed steadily, peaking at four weeks. These accumulating cells increasingly co-expressed CD206, a hallmark of alternatively activated, inflammation-resolving macrophages, and multiplex imaging showed extensive in-situ co-localization of F4/80, CD206, and APOE exclusively in tolerated grafts. A parallel enrichment of APOE-positive macrophages appeared in the spleen, lymph nodes, and bone marrow, hinting at a coordinated systemic regulatory program rather than a purely local phenomenon.

The target of this regulatory activity emerged as a specific population of tissue-resident memory CD8-positive T cells. These cells, marked by CD69 but lacking CD103, reside permanently within the graft and act as rapid-response effectors of localized rejection. The team showed that during acute rejection, this CD69-positive CD103-negative subset expanded robustly, depressing the CD4-to-CD8 ratio within the graft. As tolerance developed, however, the pool contracted and progressively upregulated the inhibitory checkpoints PD-1 and TIGIT, the classic signature of T cell exhaustion, a hyporesponsive state that limits immune-mediated tissue damage without requiring systemic T cell depletion.

Genetic proof came from transgenic experiments. When the researchers transplanted livers from APOE-knockout donors into allogeneic recipients, rejection exploded in severity. Grafts showed dense inflammatory infiltrates and structural destruction with markedly elevated Banff scores, and serum alanine and aspartate aminotransferase levels surged, reflecting profound liver injury. Flow cytometry revealed unchecked expansion of the CD69-positive CD103-negative CD8-positive tissue-resident memory population, and, crucially, the exhausted PD-1-positive and TIGIT-positive phenotype failed to appear. Without APOE, the molecular brake on alloreactivity was effectively dismantled.

In vitro co-culture experiments reinforced the causal chain. Kupffer cells harvested from wild-type mice upregulated APOE when stimulated with allogeneic T cells over 72 hours, while cells from APOE-knockout mice could not mount this response and cells engineered to overexpress APOE amplified it. When these macrophages were paired with responder splenic T cells, APOE deficiency accelerated CD8-positive T cell proliferation, whereas forced APOE overexpression blunted expansion to near baseline levels. Notably, Transwell experiments that physically separated the two cell populations showed that the suppressive effect persisted without direct contact, implying that APOE acts as a secreted immunomodulator bathing neighboring T cells in co-inhibitory signals, potentially through lipid receptors such as LRP1 or other LDL receptor family members on the T cell surface.

The study also delivered a clinically actionable finding. Analyzing preoperative serum from 31 liver transplant donors, the researchers found that higher donor APOE levels correlated negatively with recipient MELD scores and with post-operative monocyte counts, and tracked consistently with lower bilirubin and ALT levels during the first five days after surgery. Donor APOE, the authors propose, may reflect an intrinsic tolerogenic reserve of the graft, a liver inherently predisposed to a smoother immunological recovery. This positions a simple blood measurement as a potential tool for stratifying donor organs, guiding the use of marginal grafts, or identifying recipients in whom immunosuppression might be safely tapered earlier.

The work is the first to systematically assign a tolerogenic role to the APOE-positive Kupffer cell subset in transplantation, and it reframes a protein best known for cholesterol transport and Alzheimer’s disease risk as a central player in graft acceptance. The authors acknowledge limitations: mRNA abundance does not always mirror protein levels, which they addressed by anchoring key conclusions in flow cytometry and multiplex imaging, and the precise receptor that binds Kupffer-cell-derived APOE on T cells remains to be identified. Even so, the mechanistic axis they describe, in which APOE-positive macrophages recruit and exhaust pathogenic CD8-positive tissue-resident memory cells through chemokine-guided proximity and checkpoint signaling, offers a blueprint for therapies that could coax the liver’s own immune circuitry toward tolerance, potentially freeing transplant recipients from a lifetime of systemic immunosuppression.

Subject of Research: The role of APOE-positive Kupffer cells in inducing CD8-positive T cell exhaustion and immune tolerance after liver transplantation

Article Title: ApolipoproteinE + Kupffer cells maintain immune homeostasis following liver transplantation by inducing CD8 + T cell exhaustion

Article References: ApolipoproteinE + Kupffer cells maintain immune homeostasis following liver transplantation by inducing CD8 + T cell exhaustion. (n.d.). https://doi.org/10.1016/j.isci.2026.117501

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117501

Keywords: liver transplantation, Kupffer cells, apolipoprotein E, immune tolerance, T cell exhaustion, tissue-resident memory T cells, single-cell RNA sequencing, PD-1, TIGIT, macrophages, allograft rejection, transplant immunology