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

Centronuclear myopathies are a group of rare inherited disorders defined by progressive muscle wasting and weakness, named for the abnormal positioning of nuclei at the centre of muscle fibres rather than at their periphery. The most common autosomal dominant form is caused by mutations in the DNM2 gene, which encodes dynamin 2, a GTPase enzyme involved in membrane fission, intracellular trafficking and organelle morphology. Roughly 40 different heterozygous DNM2 mutations have been linked to the disease, which accounts for approximately 15 percent of all centronuclear myopathy cases. Severity ranges broadly, from mild late-onset weakness to severe neonatal forms, and no curative therapy currently exists.

In a study published in the Journal of Cachexia, Sarcopenia and Muscle, a research team used the KI-Dnm2 R465W/+ mouse model, which carries a disease-causing mutation analogous to those found in patients, to test whether inhibiting myostatin could counteract the muscle deterioration characteristic of the disease. Myostatin, also known as growth differentiation factor 8, is widely regarded as the master negative regulator of skeletal muscle mass throughout development and adult life. It signals through the activin type IIB receptor, activating the SMAD2/3 pathway, which suppresses the proliferation and differentiation of muscle precursor cells, represses the IGF1-Akt-mTOR anabolic pathway, downregulates muscle-specific genes and promotes E3 ubiquitin ligases involved in protein degradation.

The researchers first mapped the natural course of the disease in these mice using longitudinal magnetic resonance imaging, repeated at 1, 2 and 8 months of age with a high-field 7-Tesla system. Although the knockin mice were viable and grew normally in body size, their leg muscle cross-sectional area lagged dramatically behind healthy littermates. Between 1 and 2 months of age, a critical postnatal growth window, healthy mice expanded their leg muscle cross-sectional area by 1.5-fold, while the mutant mice managed only a 1.2-fold increase. Functional testing revealed that the trouble began even earlier: impaired motor coordination and reduced grip strength were already detectable at 1 month, before measurable muscle growth failure appeared, and histological analysis of the tibialis anterior muscle showed more than 20 percent of fibres displaying the hallmark central NADH-TR staining pattern of the disease at 2 months.

Digging into the molecular roots of this growth failure, the team found a coordinated disruption of multiple homeostatic systems. The number of Pax7-positive satellite cells, the stem-like reservoir that fuses with growing fibres to supply new myonuclei, was significantly reduced, along with MyoD expression, indicating defective myonuclear accretion. At the same time, the translational repressor Eif4ebp1 was upregulated, suggesting suppressed protein synthesis, while FOXO3 and its downstream E3 ligase targets MuRF1, Atrogin-1 and Musa1 were elevated, pointing to accelerated protein breakdown. Autophagy-related transcripts such as Bnip3 and Map1lc3b were paradoxically reduced while P62 and LC3B-I protein accumulated, a signature of impaired autophagic flux. Together, these findings paint centronuclear myopathy not as a single broken pathway but as a global collapse of muscle protein and nuclear homeostasis.

To test whether myostatin was a viable therapeutic target, the researchers crossed the mutant mice with a myostatin knockout line, producing double-mutant animals completely lacking functional myostatin. The results were dramatic. The double-mutant mice gained substantially more body weight, and the mass of the tibialis anterior, quadriceps, extensor digitorum longus and soleus muscles far exceeded even healthy wild-type levels. Critically, grip strength and rotarod performance, which were significantly impaired in the myopathy mice, were fully restored to normal. Because myostatin is absent from embryogenesis onward in these animals, lifelong suppression appears to be integrated into developmental muscle growth programs, including enhanced satellite cell activation and myoblast proliferation, producing stable structural and functional benefits.

Genetic deletion, however, is not a practical option for patients, so the team next turned to pharmacology. They administered a soluble activin type IIB receptor fused to a human IgG1 Fc fragment, a decoy receptor that sequesters both myostatin and activin A in the circulation, by intraperitoneal injection twice weekly at a dose of 5 milligrams per kilogram. Four-week-old mutant mice received the treatment for four consecutive weeks. The intervention produced a marked anabolic effect: tibialis anterior mass was partially restored, quadriceps mass was completely normalized, and gastrocnemius mass actually exceeded wild-type values by the end of treatment. Serum myostatin concentrations rose during therapy, consistent with the decoy receptor prolonging the circulating half-life of the bound hormone and with increased production from newly expanded muscle mass.

But the pharmacological results came with two sobering caveats. First, the muscle gains proved entirely reversible: five weeks after treatment stopped, muscle mass had fallen back to untreated disease levels, indicating that continuous administration would be required to maintain any benefit. Second, and perhaps more importantly, the drug restored size without restoring power. In situ force measurements of the tibialis anterior showed no improvement in maximal absolute or specific force despite the hypertrophy. Molecular analysis explained why: while Akt Ser473 phosphorylation increased, confirming an anabolic signal, the treatment failed to correct the core pathological features of the disease, including elevated E3 ligase expression, impaired autophagic flux, reduced ribosomal and myosin heavy chain transcripts, and dysregulated expression of excitation-contraction coupling genes such as Chrna1, RyR1 and Casq1. Because dynamin 2 is known to organize transverse tubules, the membrane invaginations that transmit electrical signals deep into the fibre, these contractile defects appear intrinsic to the disease and beyond the reach of simply growing bigger fibres.

The contrast between the two strategies carries a clear message for the field. In mice, permanent myostatin inactivation reshapes developmental programs and delivers lasting improvements in both mass and function, whereas transient pharmacological blockade produces short-lived hypertrophy that leaves the underlying contractile and metabolic defects untouched. The authors note that combined myostatin and activin A inhibition may hold particular promise for human medicine, since activin A circulates at higher levels in people than in mice and signals through the same SMAD2/3 axis. Their conclusion is that future therapies for autosomal dominant centronuclear myopathy should be judged not merely by their ability to bulk up muscle, but by whether they durably restore contractile performance, likely in combination with approaches that directly repair the excitation-contraction machinery. The work was supported by AFM-Téléthon through the strategic MyoNeurALP programme.

Subject of Research: Myostatin inhibition therapy for dynamin 2-related centronuclear myopathy

Article Title: Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2‐Related Centronuclear Myopathy Mouse Model

Article References: Anne‐Cécile, D., David, A., Mathias, V., Valentine, A., Chloé, P., Quentin, D., Esra, K., Sidney, C., Emmanuelle, G., Louise, C., Alexandre, G., Josiane, C., Aja, P., Maximilien, B., Baptiste, M., Christophe, H., Schaeffer, L., Olli, R., Marc, B., … Damien, F. (2026). Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2 ‐Related Centronuclear Myopathy Mouse Model. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70338. https://doi.org/10.1002/jcsm.70338

Image Credits: AI Generated

DOI: 10.1002/jcsm.70338

Keywords: centronuclear myopathy, myostatin, dynamin 2, sActRIIB-Fc, muscle mass, muscle force, satellite cells, autophagy, excitation-contraction coupling, mouse model, neuromuscular disease, Akt signalling