---
title: "Targeting VISTA for Skin Cancer Immunotherapy: Source Article Not Available"
id: "frontiers-in-immunology-17-targeting-vista-as-a-novel-immunotherapy-for-skin-cancer"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-targeting-vista-as-a-novel-immunotherapy-for-skin-cancer"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1815113"
published_at: "2026-09-17T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Targeting VISTA for Skin Cancer Immunotherapy: Source Article Not Available
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-targeting-vista-as-a-novel-immunotherapy-for-skin-cancer
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1815113)
- **Published At:** 2026-09-17T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source page contained only website navigation, journal navigation, and section listings from Frontiers in Immunology; the main article text and data were not present on the supplied page. - The page included repeated site menus, links to journal sections, and links for authors and submission, but no abstract, methods, results, discussion, figures, or references from the article titled about **VISTA** and **skin cancer**. - Key article metadata visible on the page included the journal name (Frontiers in Immunology) and the article URL supplied by the user; no author list, affiliations, publication date, or study specifics were reported in the source content provided. - Because the source body did not include the article text or findings, specific clinical claims, experimental results, therapeutic recommendations, and safety data were not reported and cannot be summarized or restated. - For clinicians or researchers seeking the article’s scientific content, the source suggests using the journal site navigation or the provided URL to retrieve the full article; details were not present in the supplied source. - Any interpretation, recommendations, or data that would normally be included in a full article — such as mechanism of action, preclinical or clinical evidence for **VISTA**-targeted therapy in **skin cancer**, adverse events, or trial endpoints — were not reported in the provided source and therefore are not included here. - Actionable next steps are limited to locating the complete article on Frontiers in Immunology or contacting the journal or authors; specific citation details were not available in the supplied content.
## Clinical Analysis & Structured Key Points
Frontiers | Targeting VISTA as a novel immunotherapy for skin cancer REVIEW article Front. Immunol. , 17 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1815113 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Community Series in Novel Biomarkers in Tumor Immunity and Immunotherapy: Volume III 31k views 14 articles Editor & Reviewers Edited by T M Takaji Matsutani Reviewed by L W Lily Wang M C Martin Cevallos-Cueva Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Table 1 Summary of VISTA expression patterns and clinical implications across skin cancer subtypes. View in article Table 2 Summary of key VISTA-targeted therapeutic agents in clinical and preclinical development. View in article REVIEW article Front. Immunol. , 17 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1815113 Targeting VISTA as a novel immunotherapy for skin cancer Y H Yulong Hou 1,2 X C Xi Chen 3 * C C Can Chen 1,2 * 1. Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, China 2. Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, China 3. Department of Dermatology, First Affiliated Hospital of Huzhou University, Huzhou, China See more Article metrics View details Abstract While immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized the treatment of skin cancers, a significant proportion of patients with advanced melanoma and cutaneous squamous cell carcinoma (cSCC) exhibit primary or acquired resistance. Identifying non-redundant inhibitory pathways is crucial for the next generation of immunotherapy. As a unique checkpoint, VISTA (PD-1H) maintains immune tolerance through a distinct pH-sensitive mechanism. In the acidic tumor microenvironment (TME), protonated histidine residues enhance VISTA’s binding affinity, allowing it to act as a localized guardian of immune privilege in both melanoma and cutaneous squamous cell carcinoma. By integrating molecular insights with bioengineering innovations, VISTA-directed rational combinations demonstrate significant preclinical potential to overcome immune resistance and achieve durable responses in refractory malignancies. 1 Introduction Skin cancer, including melanoma and non-melanoma types, poses a significant global health burden ( 1 , 2 ). Despite advances in diagnosis and therapy, these malignancies—especially in advanced stages—remain a deadly threat with rising global incidence, underscoring the urgent need for more effective and tolerable systemic treatments ( 3 ). The past decade has witnessed a fundamental shift in the paradigm of cancer therapy, with immunotherapy emerging as the fifth pillar of treatment, following surgery, radiotherapy, chemotherapy, and targeted therapy ( 4 , 5 ). At the heart of this revolution lies the successful application of immune checkpoint blockade (ICB) therapy, which functions by relieving suppression of the host’s anti-tumor immune response ( 6 ). Inhibitors of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) pathways have demonstrated disease-modifying potential in various cancers, capable of inducing durable responses and even clinical cures ( 7 , 8 ). In the field of skin cancer, particularly melanoma, immune checkpoint inhibitors have achieved particularly remarkable success. Long-term follow-up data from the CheckMate 067 trial showed that nivolumab combined with ipilimumab or nivolumab monotherapy for advanced melanoma provided significantly prolonged and durable survival benefits compared to ipilimumab monotherapy, with median overall survival not yet reached in the combination therapy group ( 8 ). This established immune combination therapy as the first-line standard-of-care for advanced melanoma, as recommended by American Society of Clinical Oncology (ASCO) guidelines ( 9 ). Similarly, in locally advanced and metastatic cutaneous squamous cell carcinoma (cSCC), immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have ushered in a therapeutic renaissance, offering patients a treatment option with lower toxicity and more durable responses compared to conventional chemotherapy ( 1 ). However, ICB therapy is far from a panacea. Despite historic breakthroughs, only a subset of patients benefit from existing therapies, with a substantial proportion facing primary or acquired resistance ( 10 , 11 ). In advanced melanoma, even with the most effective nivolumab plus ipilimumab regimen, a large number of patients fail to achieve long-term remission ( 12 ). This clinical challenge stems from the complex and dynamic interplay between tumors and the immune system. Tumors can evade immune clearance through multiple mechanisms, a process summarized as “cancer immunoediting,” wherein the immune system not only acts to suppress tumors but may also select more aggressive tumor clones under pressure or foster an immunosuppressive tumor microenvironment (TME), thereby promoting tumor progression ( 13 ). The TME is a complex ecosystem composed of diverse cell types, soluble factors, and physical barriers that profoundly influence the recruitment, survival, and function of effector T cells, constituting a major barrier to immunotherapy ( 14 , 15 ). Existing ICB agents, particularly combination regimens, are often accompanied by significant and potentially life-threatening immune-related adverse events (irAEs), limiting their use in broader patient populations ( 12 , 16 ). Therefore, gaining a deep understanding of the mechanisms underlying immune resistance and developing next-generation therapies to overcome these barriers are top priorities in current tumor immunology research ( 17 , 18 ). A central strategy to address these challenges is the identification and targeting of co-inhibitory immune checkpoint molecules beyond PD-1/PD-L1 and CTLA-4. A series of novel immunomodulatory receptors expressed in the TME provide a rich repository of targets for developing more effective and safer combination therapies ( 10 , 17 ). Among these emerging targets, V-domain Ig suppressor of T cell activation (VISTA) has garnered significant attention due to its unique biological properties. VISTA is primarily expressed on myeloid cells and T cells, playing a critical role in maintaining immune homeostasis and tolerance ( 17 , 19 , 20 ). Growing evidence indicates that VISTA is highly expressed in the TME of various cancers, including melanoma, and is associated with poor prognosis and immune evasion ( 19 – 21 ). In contrast to classic checkpoints like PD-1, a notable feature of VISTA is its enhanced function in acidic microenvironments (e.g., hypoxic regions of tumors), a pH-dependent regulatory mechanism that makes it an ideal target for hostile TMEs ( 10 ). This uniqueness suggests that targeting VISTA may overcome specific immune resistance mechanisms driven by the tumor’s acidic microenvironment, thereby complementing existing therapies. Preliminary preclinical studies have shown that monoclonal antibodies targeting VISTA can enhance anti-tumor immune responses and may synergize with other immunotherapies ( 10 ). Furthermore, given its unique expression patterns and regulatory mechanisms, it is hypothesized that VISTA-targeted therapeutic strategies may also help mitigate the systemic toxicities associated with traditional ICB. For instance, experimental approaches involving local delivery systems or pH-responsive nanocarriers to specifically deliver drugs to tumor sites are currently being evaluated in preclinical settings ( 21 ). To ensure a comprehensive and transparent evaluation of these emerging therapeutic strategies and the underlying biology of VISTA, a meticulous literature search was conducted across three primary electronic databases: PubMed, Web of Science, and Scopus. The search encompassed peer-reviewed articles published from database inception up to July 2026 and was restricted to the English language. The search strategy utilized combinations of keywords and Medical Subject Headings (MeSH) terms, including (“VISTA” OR “V-domain Ig suppressor of T cell activation” OR “PD-1H”) AND (“skin cancer” OR “melanoma” OR “cutaneous squamous cell carcinoma”) AND (“immunotherapy” OR “immune checkpoint” OR “tumor microenvironment”). By synthesizing the identified literature, this review aims to provide a robust and unbiased overview of VISTA’s unique molecular mechanisms, its dynamic role within the skin cancer microenvironment, and the promising trajectory of VISTA-targeted interventions. 2 The molecular biology, structure, and pH-sensitive regulation of VISTA VISTA, also known as PD-1H, is a type I transmembrane protein belonging to the B7/CD28 immune checkpoint family, yet it exhibits limited homology to other members, conferring unique structural and functional attributes ( 22 , 23 ). As originally delineated in the landmark discovery study by Wang et al., VISTA was initially identified through a genomic database search using the immunoglobulin variable (IgV) region of PD-1 and was recognized for its ability to suppress T cell-mediated immune responses ( 24 ). Unlike classical checkpoints such as PD-1 and CTLA-4, which are primarily induced upon T cell activation, VISTA is constitutively expressed on resting naïve T cells and across the myeloid lineage, including macrophages, dendritic cells, and neutrophils, positioning it as a critical homeostatic regulator of both innate and adaptive immunity ( 23 , 25 , 26 ). This foundational expression pattern underpins its distinct role in maintaining peripheral tolerance and modulating inflammatory responses, setting the stage for its complex involvement in cancer immunology. The three-dimensional structure of the human VISTA extracellular domain, resolved at high resolution, reveals a canonical IgV-like fold but with several distinctive features that are central to its function ( 27 , 28 ). A hallmark of VISTA’s structure is its elongated CC’ loop and an unusually high content of surface-exposed histidine residues clustered in the complementarity-determining region (CDR)-like proximal half of the molecule ( 27 ). These histidine clusters are functionally critical for VISTA’s coinhibitory activity. The protonation state of these histidines is sensitive to pH changes, a property that directly influences VISTA’s binding interactions. In the slightly acidic microenvironment typical of solid tumors, these histidine residues become protonated, enhancing VISTA’s binding affinity. This pH-sensitive switch is a key molecular mechanism that allows VISTA to exert potent immunosuppressive effects precisely within the acidic tumor niche ( 29 ) ( Figure 1 ). Furthermore, VISTA’s IgV domain possesses a non-canonical topology, including an extra ‘H’ β-strand and a unique ‘clamping’ disulfide bond not found in other IgV-like structures, which likely restricts its orientation on the cell surface ( 27 ). Two additional disulfide bonds stabilize the core of the domain, contributing to its structural integrity and distinguishing it from other B7 family members ( 28 ). Figure 1 Molecular mechanism of VISTA as a pH-responsive immunological switch. This unique structural arrangement defines the functional binding epitopes on VISTA. A contiguous binding region, encompassing the extended CC’ loop and an attached helix, forms the critical epitope for interaction with both functional binding partners and therapeutic antibodies ( 28 ). For instance, the binding site for V-Set and Immunoglobulin domain containing 3 (VSIG3), a putative receptor, overlaps with this region ( 28 ). The pH-dependent activity is strategically exploited by next-generation therapeutic agents. The pH-selective antibody SNS-101 is engineered to bind with high affinity to VISTA specifically in the acidic TME while showing minimal binding at physiological pH. This selectivity is achieved by targeting an epitope dependent on the protonation of key histidine residues, which confers a superior pharmacokinetic and safety profile by reducing on-target, off-tumor binding in healthy tissues ( 29 ). This rational design underscores the importance of understanding VISTA’s pH-sensitive interface for developing safer and more effective therapeutics. The receptor-ligand landscape for VISTA is complex and context-dependent, involving both cis- and trans-interactions. VISTA can function as both a receptor on T cells and a ligand expressed on antigen-presenting cells or tumor cells ( 22 , 30 ). Several binding partners have been proposed. P-selectin glycoprotein ligand-1 (PSGL-1) expressed on T cells can interact with VISTA. VSIG3 and VSIG-8 have also been identified as potential receptors or binding partners for VISTA ( 28 , 31 , 32 ). However, the physiological relevance of VSIG3 as a bona fide receptor remains highly controversial. Notably, Johnston et al. reported conflicting data, demonstrating that VISTA fails to bind to VSIG3 on the cell surface under any pH conditions (ranging from acidic to neutral). This critical finding questions the validity of initial biochemical reports and suggests that earlier observations might be artifacts of soluble protein assays rather than reflecting true cell-surface dynamics ( 33 ). Consequently, the field is increasingly shifting focus toward PSGL-1 and LRIG1 as the more definitive and physiologically relevant functional receptors for VISTA. The interaction between VISTA and VSIG-8 can suppress interleukin-2 (IL-2) production, and disruption of this interaction with a small molecule inhibitor has been shown to promote T cell cytokine production and inhibit melanoma growth in preclinical models ( 31 ). More recently, leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) was identified as a direct T cell-expressed binding partner for VISTA ( 34 ). The VISTA-LRIG1 interaction delivers an inhibitory signal that suppresses T cell receptor (TCR) signaling pathways. Genetic deletion of LRIG1 in T cells led to enhanced antitumor cytotoxic T lymphocyte (CTL) responses, characterized by expanded effector and memory-like populations, highlighting this axis as a critical downstream mechanism of VISTA-mediated suppression ( 34 ) ( Figure 2 ). Additionally, extrapolating from research in other malignancies, VISTA can engage in heterophilic interactions, such as recognizing galectin-9 (Gal-9) secreted by tumor cells like acute myeloid leukemia blasts. While yet to be fully validated in the specific context of skin cancer, this VISTA-Gal-9 interaction can trigger intracellular granzyme B activation and apoptosis in cytotoxic T cells, representing a direct cytotoxic mechanism of immune evasion ( 35 ). The expression dynamics within the TME are interconnected, as evidenced in breast cancer where knockdown of one member of the VISTA/VSIG3/PSGL-1 axis upregulated the expression of the others, suggesting compensatory regulation ( 32 ). Figure 2 The multi-faceted interaction network of VISTA in immune suppression. The expression of VISTA is regulated at multiple levels, including transcriptional, epigenetic, and metabolic pathways. In various cancers, including melanoma, ovarian, and endometrial cancers, VISTA expression on tumor cells themselves has been documented and linked to immune suppression ( 30 , 36 ). In endometrial cancer, the methylation status of the VISTA promoter region influences its expression, pointing to epigenetic control ( 30 ). A significant regulatory axis involves the aryl hydrocarbon receptor (AHR). The AHR, a ligand-activated transcription factor, can be engaged by endogenous metabolites like kynurenine (a tryptophan catabolite) produced by tumor cells ( 37 ). Activation of this AHR pathway promotes VISTA expression. In melanoma cells, VISTA levels were shown to be under the control of AHR, as AHR knockdown or inhibition dramatically reduced VISTA expression ( 36 ). This link is therapeutically relevant, as the anti-diabetic drug metformin was found to suppress both AHR and VISTA expression in melanoma models ( 36 , 38 ). Another metabolic regulator is aldehyde dehydrogenase 2 (ALDH2). ALDH2-mediated detoxification of endogenous aldehydes was found to sustain VISTA expression by activating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB) signaling pathway. Genetic or pharmacological inhibition of ALDH2 downregulated VISTA, revitalized CD8+ T cell function, and synergized with ICB ( 39 ). Functionally, VISTA exerts its immunosuppressive effects through diverse mechanisms on different immune cell compartments. On naïve T cells, VISTA acts as a critical checkpoint for maintaining quiescence and peripheral tolerance. Loss of VISTA disrupts the quiescent naïve T cell pool, leads to accumulation of spontaneously activated T cells, and, in genetically susceptible backgrounds, dramatically enhances autoimmunity, indicating its non-redundant role in setting the threshold for T cell activation ( 25 , 40 ). Its agonistic engagement can promote antigen-induced peripheral T cell deletion, reinforcing tolerance ( 25 ). On myeloid cells, VISTA functions as a potent regulator of innate inflammation. VISTA agonism can transcriptionally and epigenetically re-program macrophages towards a tolerant and anti-inflammatory phenotype, augmenting lipopolysaccharide (LPS) tolerance and reducing the production of pro-inflammatory cytokines like TNF and IL-6 ( 26 ). This dual role in restraining both naïve T cell responses and innate inflammation underscores VISTA’s function as a broad immune homeostat. However, under inflammatory conditions such as those in the TME, VISTA’s restraint on T cells can be overcome, yet its expression on myeloid cells and tumor cells continues to suppress antitumor immunity ( 22 , 25 ). This multifaceted functionality necessitates precise therapeutic targeting strategies—antagonism to block its inhibitory signals in cancer versus agonism to suppress pathological inflammation in autoimmune settings ( 23 , 41 ). 3 Expression patterns and functional roles of VISTA in the skin cancer TME Building upon its unique molecular biology and pH-sensitive regulation, the expression of VISTA within the TME of skin cancers reveals a complex and context-dependent role in immune modulation. Its pattern of expression is not uniform across different skin cancer subtypes or even within individual tumors, reflecting the heterogeneous nature of the immune landscape. In cutaneous melanoma, VISTA expression is observed on both immune and tumor cells, a duality that informs its functional impact. Single-cell RNA sequencing of acral melanoma, a subtype with a notoriously immunosuppressive microenvironment, revealed that VISTA was expressed in a significant 58.3% of myeloid cells, highlighting its prominence on this immunosuppressive compartment ( 42 ). TIGIT was more associated with T/natural killer (NK) cells ( 42 ). This study also noted that acral melanomas were characterized by lower overall immune infiltrate and fewer effector CD8+ T cells compared to non-acral cutaneous melanomas, situating VISTA-expressing myeloid cells within a broadly suppressed immune context ( 42 ). Beyond immune cells, melanoma cell-intrinsic expression of VISTA is regulated by the stemness factor Forkhead box D3 (FOXD3) ( 43 ). BRAF inhibition upregulates FOXD3, which in turn transcriptionally represses VISTA, creating a dynamic link between oncogenic signaling pathways and checkpoint expression ( 43 ). Functionally, tumor cell-specific VISTA expression promotes tumor onset in vivo , correlating with increased intratumoral regulatory T cells (Tregs) and enhanced PD-L1 expression on tumor-infiltrating
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