The molecule at the centre of the story, V-domain Ig suppressor of T cell activation, or VISTA, belongs to the B7 family of immune-regulatory ligands. Immunologists first characterised it as a negative regulator of T cell responses, and subsequent work established it as a bona fide immune checkpoint alongside better-known targets such as PD-1 and CTLA-4. In many cancers, high VISTA expression has been associated with immunosuppressive tumour microenvironments and, in several tumour types, with poorer clinical outcomes. Immune checkpoint inhibitors that unleash T cells have already transformed the treatment landscape for mesothelioma: the CheckMate 743 trial demonstrated that first-line nivolumab plus ipilimumab improves survival in unresectable malignant pleural mesothelioma compared with platinum-based chemotherapy. Yet responses are far from universal, and the disease continues to claim tens of thousands of lives globally each year, a burden compounded by incomplete mortality data and continuing occupational asbestos exposure in many countries.

What makes the new study striking is that it reframes VISTA not primarily as a saboteur of anti-tumour immunity but as an intrinsic growth driver within the cancer cells themselves. The team began by mining The Cancer Genome Atlas mesothelioma cohort, which revealed that VISTA and its B7-family relative B7-H3 are both highly expressed in mesothelioma. Intriguingly, their expression patterns diverged along histological lines: VISTA levels correlated positively with genes characteristic of the epithelioid subtype, the most common form of the disease, whereas B7-H3 expression tracked with genes enriched in sarcomatoid tumours, the more aggressive and treatment-resistant variant. This subtype-specific patterning hinted that the two molecules might play distinct biological roles rather than functioning as interchangeable markers of immune evasion.

To test whether VISTA does anything functional in mesothelioma cells, the researchers turned to cell lines and genetic manipulation. When they overexpressed VISTA, the mesothelioma cells proliferated more vigorously. When they knocked the gene down, proliferation dropped markedly, an effect that held both in vitro and in a mouse xenograft model, where silencing VISTA significantly suppressed tumour growth in vivo. These are not trivial results. They demonstrate that a molecule celebrated for dampening immune attacks is simultaneously operating as an oncogenic asset inside the tumour, promoting cell division through mechanisms that have nothing to do with evading T cells.

Uncovering those mechanisms required two complementary high-throughput approaches. First, the team performed immunoprecipitation followed by mass spectrometry to catalogue the proteins that physically associate with VISTA inside mesothelioma cells. The proteomic profiling revealed interactions with cell adhesion molecules and with intracellular signalling proteins, most notably receptor-interacting serine/threonine-protein kinase 1, or RIPK1. RIPK1 is a fascinating and clinically scrutinised node in cellular signalling, sitting at the crossroads of inflammation and cell death pathways and increasingly regarded as a druggable target in its own right. Its presence in a VISTA-associated complex suggests that the checkpoint protein is wired into core signalling circuitry that governs cell survival and proliferation, rather than merely decorating the cell surface for immunological purposes.

Second, RNA sequencing of cells with altered VISTA levels mapped the downstream transcriptional consequences. The analysis showed enrichment of TNF signalling among the genes whose expression changed, pointing to a reprogramming of inflammatory response pathways within the tumour cells. Functional assays then delivered the mechanistic punchline: VISTA expression enhanced phosphorylation of AKT, also known as protein kinase B, a central hub of the PI3K signalling cascade that promotes cell growth, survival and proliferation in many cancers. Together, the proteomic and transcriptomic data sketch a coherent model in which VISTA, through its interactions with adhesion molecules and RIPK1 and its modulation of TNF-related programmes, amplifies AKT-dependent signalling that drives mesothelioma cells to divide.

The concept of tumour-intrinsic immune checkpoint signalling is not entirely without precedent. PD-L1, the ligand for PD-1, has been shown to carry an intracellular signalosome in cancer cells that can influence autonomous growth and resistance to therapy, and recent work has implicated VISTA itself in intrinsic growth regulation in other malignancies, including a report that a short intracellular motif of VISTA can block growth receptor signalling in certain cancer cells. The mesothelioma findings extend this emerging paradigm and add an important nuance: in this disease, VISTA appears to do the opposite, actively promoting proliferation. The directionality of the effect may depend on cellular context, downstream partners or the intracellular motifs engaged, questions that will likely occupy the field as the biology is dissected further.

Therapeutically, the implications are considerable. If VISTA drives tumour growth through cell-autonomous signalling, then blocking it could deliver a double blow, simultaneously releasing the brakes on anti-tumour T cells and starving the cancer cells of an internal growth signal. Several anti-VISTA antibodies are already in clinical development, and imaging studies using radiolabelled anti-VISTA agents are helping to characterise the target in patients. The new data argue that mesothelioma, particularly the epithelioid subtype in which VISTA expression is enriched, should be considered a priority indication for such agents. They also raise the possibility of combination strategies, pairing VISTA blockade with existing checkpoint inhibitors or with agents that target the AKT pathway or RIPK1 signalling, though such hypotheses will need to be tested rigorously in preclinical and clinical settings.

Caveats remain, as they always do in translational research. The study relies on cell lines, xenografts and retrospective analysis of a public genomic dataset; whether VISTA expression predicts outcome in mesothelioma patients, and whether pharmacological blockade of the molecule slows tumours in humans, are questions that only clinical trials can answer. The precise molecular choreography linking VISTA, RIPK1, TNF signalling and AKT phosphorylation also awaits detailed structural and biochemical definition. Moreover, VISTA is known to bind ligands such as PSGL-1 and VSIG-3 in an acidic, pH-sensitive manner, and the interplay between these extracellular interactions and the intracellular signalling uncovered here is an open puzzle.

Even so, the study adds a compelling new character to the mesothelioma story and exemplifies a broader shift in immuno-oncology thinking: checkpoint molecules are not merely handles for immune manipulation but signalling platforms in their own right, embedded in the growth machinery of the tumours that display them. For a cancer that has seen only incremental therapeutic progress for decades, the identification of a druggable molecule that is both highly expressed and functionally required for tumour proliferation is the kind of finding that can reshape research agendas. As clinical programs against VISTA mature, mesothelioma patients, who have waited a long time for genuinely new options, may finally stand to benefit from a target that works on both sides of the tumour’s defences.

Subject of Research: Tumour-intrinsic proliferative signalling by the immune checkpoint molecule VISTA in mesothelioma

Article Title: VISTA drives tumour-intrinsic proliferation in mesothelioma cells

Article References: VISTA drives tumour-intrinsic proliferation in mesothelioma cells. (n.d.). https://doi.org/10.1038/s41416-026-03639-z

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03639-z

Keywords: mesothelioma, VISTA, immune checkpoint, B7-H3, RIPK1, AKT signalling, TNF signalling, tumour-intrinsic proliferation, TCGA, xenograft, immunotherapy, British Journal of Cancer

What distinguishes VISTA from checkpoint molecules such as PD-1 and CTLA-4 is where it acts and how it is deployed. In many human malignancies, VISTA is preferentially enriched not on tumor cells themselves but on the innate immune cells that populate the tumor microenvironment, including tumor-associated macrophages, myeloid-derived suppressor cells and dendritic cells. This compartment-specific distribution matters because these myeloid populations orchestrate much of the immune suppression that characterizes so-called cold tumors. When VISTA is abundant on these cells, the result is suppressive myeloid differentiation, impaired antigen presentation, altered inflammatory cytokine programs and, ultimately, T-cell dysfunction and immune exclusion, the physical and functional exclusion of cytotoxic T lymphocytes from the tumor bed.

The structural biology of VISTA helps explain its unusual behavior. Like PD-L1, it belongs to the B7 family of immunoregulatory molecules, but it possesses distinctive features, including an acidic pH-selective binding mode. Landmark work published in Nature in 2019 demonstrated that VISTA functions as an acidic pH-selective ligand for PSGL-1, meaning its suppressive signaling is most active in the hypoxic, lactate-rich, acidic conditions that prevail inside solid tumors. This pH dependence effectively arms VISTA precisely where tumors are most aggressive and where other therapies struggle, and it may underlie the molecule’s contribution to resistance against PD-1 and CTLA-4 blockade in selected settings.

The receptor web surrounding VISTA extends well beyond PSGL-1. Subsequent studies have identified additional binding partners, including VSIG-3, which inhibits human T-cell function upon engagement, galectin-9, which cooperates with VISTA to suppress cytotoxic T lymphocyte activity, and LRIG1, which engages VISTA on dendritic cells and impairs tumor-specific CD8-positive T-cell responses. A recent study also revealed that a four-amino-acid intracellular motif of VISTA can block growth receptor signaling within cancer cells themselves, indicating that the molecule can exert tumor-intrinsic effects in addition to its immunoregulatory ones. Which of these ligand interactions dominates in living tumors remains an open question and one of the key unresolved issues highlighted by the review authors.

Evidence from preclinical models has been particularly revealing about the myeloid dimension. Research published in Cancer Immunol Res showed that VISTA controls antitumor immunity by regulating myeloid cell-mediated inflammation and immunosuppression, while a 2024 study in Cell Reports demonstrated that VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells through STAT3- and polyamine-dependent mechanisms. Hypoxia itself induces VISTA expression on myeloid-derived suppressor cells, amplifying their suppressive function. Work on tumor-associated macrophages has shown that VISTA drives these cells toward a pro-tumoral phenotype that promotes cancer cell phagocytosis while down-regulating T-cell responses, and that targeting a conserved population of TIM3-positive, VISTA-positive macrophages can overcome resistance to cancer immunotherapy.

The clinical relevance of this biology is increasingly documented across tumor types. In prostate cancer, VISTA expression was found to increase after ipilimumab therapy, positioning it as a mechanism of adaptive resistance. Comparative analyses of melanoma and pancreatic cancer identified VISTA as a potential target in the notoriously immunotherapy-resistant pancreatic setting, and elevated VISTA has been reported in gastric and colorectal carcinomas, oral squamous cell carcinoma, cervical carcinoma and non-small cell lung cancer. In metastatic melanoma, VISTA upregulation has been linked to acquired resistance to anti-PD-1 therapy. Intriguingly, the prognostic picture is not uniform: in triple-negative breast cancer, VISTA expression on immune cells correlated with favorable outcome, underscoring the review’s central argument that cellular source and spatial localization determine the biological and prognostic meaning of VISTA measurements.

Therapeutic strategies targeting VISTA have advanced into early clinical testing. The oral small-molecule inhibitor CA-170, derived from a PD-1 sequence, exhibited preclinical antitumor efficacy, although debate persists about its precise molecular targets. More refined approaches include KVA12123, a highly potent anti-VISTA antibody described as promising against poorly immunogenic tumors and currently in phase 1/2 testing alone and in combination with pembrolizumab in patients with advanced solid tumors, and HMBD-002, an IgG4 monoclonal antibody evaluated in a first-in-human phase 1 trial. A pH-selective antibody termed SNS-101 has been engineered to activate preferentially in the acidic tumor microenvironment, enhancing PD-1 pathway responses while limiting systemic exposure. Rationally designed antibodies that blockade the C-C’ loop region of VISTA have been shown to reverse immune suppression and remodel the immune microenvironment in an Fc-independent manner.

Combination approaches reflect the conviction that VISTA operates in parallel to, rather than downstream of, classical checkpoints. Bifunctional small molecules simultaneously targeting PD-L1 and VISTA have shown favorable pharmacokinetics in preclinical development, dual silencing of tumor-intrinsic VISTA and CTLA-4 has stimulated T-cell mediated responses in breast cancer models, and VISTA blockade has been shown to enhance the efficacy of radiotherapy in murine melanoma and adenocarcinoma models. Nanoparticle-based delivery systems targeting VISTA have induced potent antitumor immunity in preclinical studies, and chemotherapy itself has been shown to induce VISTA expression in tumor cells via HIF-2alpha, suggesting that sequencing VISTA-directed therapy with cytotoxic treatment could be clinically important.

Technological advances are reshaping how researchers interrogate VISTA biology. Spatial transcriptomics, multiplexed imaging platforms such as CODEX and imaging mass cytometry now allow investigators to map VISTA expression at single-cell resolution within intact tissue architecture, addressing precisely the questions of cellular source and spatial localization that the review identifies as central. Such compartment-resolved analysis may improve prognostic interpretation, biomarker development and patient selection for VISTA-directed therapies, moving the field beyond simple expression quantification toward a functional understanding of where, when and in whom the pathway matters.

The reviewers conclude that VISTA should be regarded as a dynamically regulated, myeloid-centered checkpoint axis rather than a redundant inhibitory receptor, with translational relevance concentrated in checkpoint-refractory and immune-excluded tumors. Whether early pharmacodynamic evidence of target engagement will convert into durable clinical benefit remains the decisive unanswered question, but as combination trials mature and spatial profiling sharpens patient stratification, VISTA is emerging as one of the most compelling next-generation targets in cancer immunotherapy, potentially unlocking treatment for the many patients whom PD-1 and CTLA-4 blockade have so far failed.

Subject of Research: VISTA immune checkpoint biology in myeloid cells and its therapeutic targeting in cancer

Article Title: VISTA as a myeloid-centered checkpoint axis in cancer: biology, tumor microenvironment, and therapeutic implications

Article References: Tekiner, S., Karataş, R. B., Alras, Y., Zıkşahna, K., Merdan, S., & Ihlamur, M. (2026). VISTA as a myeloid-centered checkpoint axis in cancer: biology, tumor microenvironment, and therapeutic implications. Medical Oncology, 43(10), Article 280. https://doi.org/10.1007/s12032-026-03416-1

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03416-1

Keywords: VISTA, VSIR, immune checkpoint, myeloid cells, tumor microenvironment, tumor-associated macrophages, myeloid-derived suppressor cells, cancer immunotherapy, checkpoint resistance, PSGL-1, acidic pH, antibody therapy

VSIR, also called VISTA, is a type I transmembrane protein of the B7/CD28 family. Immunologists have long studied it for its immunosuppressive functions within the tumor microenvironment, where it attenuates effector T cell activation, fosters regulatory T cell expansion, and supports the suppressive activity of myeloid-derived suppressor cells and tumor-associated macrophages. But recent work has documented frequent upregulation of VSIR on tumor cells themselves across multiple cancer types, and in melanoma, tumor-cell-specific VSIR expression has been shown to promote tumor onset in preclinical models. In gastric cancer, elevated VSIR correlates with advanced stage, lymph node metastasis, and poor clinical outcomes. These observations raised an provocative question: could VSIR, beyond its checkpoint role, be driving tumor progression through mechanisms intrinsic to the cancer cell? The research team, led by Jinshan Liu, Guoquan Huang, and colleagues at institutions affiliated with Chongqing Medical University, set out to answer it by searching for the signaling pathways that VSIR might control.

Their attention soon turned to AXL, a receptor tyrosine kinase of the TAM family that has emerged as a central regulator of tumor progression, metastasis, and therapeutic resistance across many cancers. When bound by its ligand GAS6, AXL activates the PI3K/AKT, MAPK/ERK, and STAT3 pathways, enhancing cell survival, epithelial-mesenchymal transition, and immune evasion. In gastric cancer, AXL overexpression has been documented in both cell lines and patient specimens and is associated with aggressive phenotypes including peritoneal dissemination. Mining The Cancer Genome Atlas stomach adenocarcinoma cohort through the GEPIA2 platform, the researchers confirmed that AXL expression climbs steadily with tumor stage and that patients with high AXL levels suffer significantly worse overall survival, with a hazard ratio of 1.4. The clinical signal was unmistakable, but the regulatory circuitry that produces AXL overexpression in an inflammatory setting had not been mapped.

The team’s first mechanistic clue came from transcriptome sequencing of gastric cancer cells. When HGC-27 gastric cancer cells were engineered to overexpress VSIR and then stimulated with LPS to mimic bacterial inflammation, AXL mRNA levels rose dramatically. The effect was strikingly conditional: without LPS, VSIR overexpression alone failed to induce AXL, but once the inflammatory stimulus was applied, VSIR markedly enhanced AXL transcription. Conversely, silencing VSIR with two independent small interfering RNAs abolished the LPS-driven induction of AXL at both the mRNA and protein levels. The results established VSIR as both necessary and sufficient, within the inflammatory context, to promote AXL expression, forging a direct molecular link between innate immune signaling and AXL-driven tumor progression.

To identify the transcription factor mediating this effect, the researchers cross-referenced four independent prediction databases—hTFtarget, CHEA, FIMO_JASPAR, and ENCODE—and found that two candidates, STAT3 and EGR1, were consistently predicted to bind regulatory regions of the AXL gene. Chromatin profiling from the Cistrome Database revealed strong enrichment of STAT3-binding signals at an enhancer upstream of AXL, coinciding precisely with the active histone marks H3K27ac and H3K4me1, the biochemical signatures of functional enhancer elements. Chromatin immunoprecipitation followed by quantitative PCR in HGC-27 cells confirmed that STAT3 physically occupies this enhancer region. The evidence became causal when the team cloned the enhancer fragment into a luciferase reporter: co-transfection with a STAT3 expression plasmid dramatically boosted reporter activity, while site-directed mutation of the predicted STAT3-binding motif, changing the sequence CAT CTG GAA AG to ACC ACA ACC CA, abolished that activation. Knocking down STAT3 with siRNA reduced endogenous AXL mRNA and protein, and parallel experiments in mouse bone marrow-derived macrophages showed that LPS-induced AXL upregulation was completely eliminated when STAT3 was depleted. Together, these experiments established STAT3 as the essential transcriptional mediator linking LPS stimulation to AXL expression in both myeloid and cancer cells.

But how does VSIR, a membrane checkpoint protein, activate STAT3? The answer, the researchers found, lies in the IL-6 pathway. Under LPS stimulation, VSIR-overexpressing cells produced substantially more IL-6 mRNA, and western blotting revealed enhanced phosphorylation of STAT3—without any measurable change in the phosphorylation of p65 or JAK1, indicating a specific rather than generalized activation of inflammatory signaling. When the team silenced TLR4, the VSIR-driven boost in IL-6 production vanished, placing VSIR functionally downstream of the TLR4 receptor. The emerging picture is a coherent cascade: LPS engages TLR4, VSIR potentiates IL-6 release, IL-6 activates STAT3, and STAT3 directly switches on AXL transcription.

Remarkably, transcription proved to be only half the story. Co-immunoprecipitation experiments revealed that VSIR physically interacts with the AXL protein itself, and immunofluorescence microscopy confirmed the colocalization of the two molecules in both HGC-27 and MKN-45 gastric cancer cells. Cycloheximide chase assays, which track protein decay over time, demonstrated that VSIR overexpression significantly prolongs the half-life of AXL. The proteasome inhibitor MG132 erased the difference in AXL levels between VSIR-proficient and VSIR-deficient cells, pointing to the ubiquitin-proteasome pathway as the route of degradation, and direct ubiquitination assays showed that VSIR overexpression markedly attenuates the polyubiquitination of endogenous AXL. In other words, VSIR both writes more AXL mRNA and protects the resulting protein from destruction, a dual mechanism that ensures robust, sustained AXL signaling precisely when inflammatory conditions would otherwise favor tumor growth.

Clinical validation came from multiplex immunofluorescence staining of patient tissues, including samples from twelve gastric cancer patients treated at the First Affiliated Hospital of Chongqing Medical University. Tumor samples showed a significant positive correlation among VSIR, AXL, and phosphorylated STAT3, mirroring the in vitro findings. More striking still, when the team compared HER2-positive tumors from patients resistant to HER2-targeted therapy, treatment-naive HER2-positive tumors, HER2-negative tumors, and normal gastric mucosa, the fraction of cells simultaneously positive for VSIR, AXL, and HER2 was markedly highest in the resistant HER2-positive group. Because elevated VSIR and AXL were also present in treatment-naive HER2-positive tumors, the authors conclude that this co-expression pattern is a general feature of HER2-positive gastric cancer rather than a specific marker of acquired resistance—implying that these tumors depend on dual engines of growth: HER2-driven proliferation and VSIR-driven, AXL-mediated survival.

The therapeutic implications were tested directly in a subcutaneous xenograft model in nude mice, with animals randomized into five treatment groups. VSIR overexpression robustly accelerated tumor growth, and while the HER2 inhibitor tucatinib alone produced only modest suppression, the AXL inhibitor AXL-IN-13 sharply curtailed VSIR-driven tumor expansion, reducing tumor volume and weight to levels comparable to or below controls. The dual blockade of HER2 and AXL produced the most potent anti-tumor effect of all, nearly abolishing the pro-tumorigenic activity of VSIR, with Ki-67 immunohistochemistry confirming sharply reduced proliferation in the treated tumors. Rescue experiments in vitro reinforced the causal chain: when VSIR was knocked down in MKN-45 cells, migration and invasion declined sharply, but re-expressing AXL restored these metastatic capabilities. Taken together, the study recasts VSIR as a tumor-intrinsic oncogenic amplifier that operates independently of its immune checkpoint function, positions the VSIR-AXL axis as a druggable vulnerability in an inflammation-associated malignancy, and supplies a strong preclinical rationale for combining AXL inhibitors with HER2-directed therapy in patients whose tumors currently escape single-agent blockade.

Subject of Research: The role of VSIR in regulating AXL expression and promoting gastric cancer proliferation through inflammatory STAT3 signaling

Article Title: Mechanistic insights into VSIR-mediated AXL regulation and gastric cancer proliferation

Article References: Liu, J., Huang, G., Li, Y., Tan, Y., Qin, B., Hao, C., Peng, J., Zhu, H., Zhang, B., Cheng, Y., & Qian, K. (2026). Mechanistic insights into VSIR-mediated AXL regulation and gastric cancer proliferation. iScience, 29(10), Article 117580. https://doi.org/10.1016/j.isci.2026.117580

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117580

Keywords: gastric cancer, VSIR, VISTA, AXL, STAT3, IL-6, TLR4, Helicobacter pylori, HER2, immune checkpoint, protein stability, targeted therapy