Objective: To investigate the clinicopathological and genetic characteristics of mesenchymal tumors with GLI1 gene alterations. Methods: Five cases diagnosed at the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China from 2021 to 2025 were collected. HE and immunohistochemical slides were reviewed. Tumor-associated genetic alterations were detected using a next generation sequencing (NGS) panel of pan-solid tumor genes (468 genes, 116 DNA+352 RNA). Fluorescence in situ hybridization (FISH) was performed to detect GLI1 gene translocation and amplification. Clinical and follow-up data were analyzed. Results: There were 3 females and 2 males, aged 48, 16, 47, 47 and 37 years, respectively. The tumor locations were the tongue, small intestine, ovary, and buttock. Histologically, tumor cells arranged in nest and lobular arrangements; within a partially myxoid stroma with necrosis and calcification, surrounded by a rich fibrovascular network around and a pseudocapsule in some cases. The tumor cells were predominantly round to oval, with fewer short spindled forms, showing mild to moderate atypia and distinct nucleoli. Immunohistochemically, tumor cells variably expressed CD56, S-100, and smooth muscle actin, but were negative for broad-spectrum epithelial markers. GLI1 immunohistochemistry showed diffuse, strong positivity (2 cases stained). Ki-67 proliferation index ranged from 1% to 30%. NGS identified PTCH1::GLI1 fusions in three cases and GLI1 amplification in two. All patients underwent complete surgical resection without adjuvant therapy. During the follow-up (4-16 months), one case recurred, while four remained disease-free. Conclusions: Mesenchymal neoplasm with GLI1 gene alterations is a type of tumor with low malignant potential, representing the biological behavior of low-grade sarcoma. However, it is currently not recognized by the World Health Organization classification. Surgical resection is the preferred treatment. While immunophenotyping lacks specificity, and GLI1 immunohistochemistry could aid in its diagnosis. Definitive diagnosis and differential diagnosis of this tumor require characteristic morphological features combined with molecular confirmation of GLI1 gene fusion or amplification.

Objective: To investigate the clinical application of DDIT3 gene rearrangement using fluorescence in situ hybridization (FISH) in myxoid liposarcoma (MLPS) and to analyze the cases with atypical signal pattern. Methods: A total of 386 cases were examined for DDIT3 gene rearrangement using FISH in the West China Hospital, Sichuan University, Chengdu, China from January 2018 to December 2024. The clinicopathologic data and molecular detection results were collected. Six MLPS with DDIT3 cryptic rearrangement (CR-MLPS) were identified and subject to FISH testing of FUS and EWSR1 break, EWSR1::DDIT3 and FUS::DDIT3 fusion, next-generation sequencing (NGS), reverse-transcriptase polymerase chain reaction and Sanger sequencing. Results: Among the 386 successfully tested cases, 154 cases were histologically diagnosed as MLPS, of which 148 (148/156, 96.1%) were positive for DDIT3 gene rearrangements. In the positive cases, 57 cases were further subject to FUS and EWSR1 break-apart examination. Among them, 51 cases (51/57, 89.5%) showed FUS rearrangements, 5 cases (5/57, 8.8%) displayed EWSR1 rearrangements and 1 case was negative for FUS and EWSR1 rearrangement. DDIT3 gene rearrangements were negative in 238 cases (238/386, 59%). Six CR-MLPS were identified, including two females and four males, with an average age of 32 (14, 55) years, all located in the deep soft tissues of the extremities. All six cases of CR-MLPS presented typical MLPS morphology, with nodular distribution, abundant mucin, and visible branched capillaries. The cells were round and of medium size. Adipoblasts and cells with adipocyte-differentiation were also observed. The tumor cells in all six cases of CR-MLPS were negative or focally positive for S-100, and negative for p63 (4/4) and CDK4 (3/3). The Ki-67 index was 10% to 15%. Three of the six DDIT3 CR-MLPS showed small gap of DDIT3 break, one case revealed centromeric amplifications of DDIT3 gene, and two cases displayed 1 to 3 yellow/fusion signals. Subsequent FISH fusion test, reverse-transcriptase polymerase chain reaction and NGS confirmed that four cases had EWSR1::DDIT3 variants and two cases had FUS::DDIT3 variants. All six patients underwent surgical resection followed by radiotherapy. Among them, one patient had a recurrence 4 years after surgery, and another had recurrence and metastasis. Conclusions: FISH detection of DDIT3 gene rearrangements is important for the diagnosis of MLPS, whereas a small number of cases may still be missed due to cryptic rearrangement. The CR-MLPS cases present typical morphology, among which the EWSR1::DDIT3 variants are more commonly detected than the others.

In conjunction with the new 2025 ISSVA classification, this article interprets the classification of this group of diseases one by one and elaborates on clinical and pathological issues related to the new classification. It aims to provide a reference for the accurate classification and diagnosis of vascular anomalies diseases from a pathological perspective and further enhance pathologists' in-depth understanding.

Solid pseudopapillary tumor of the pancreas (SPTP) is a rare pancreatic neoplasm of low malignant potential. It predominantly affects young women and raises ongoing questions about its origin and behavior. We aimed to evaluate somatic mutations of the β-catenin (CTNNB1) gene in Mexican patients with SPTP and assess clinical and molecular genotype-phenotype correlations in this rare tumor.

A cross-sectional study of SPTP patients (1997-2023) was conducted at a tertiary care medical center. Tumor and non-affected pancreatic tissue samples underwent staining, immunohistochemistry testing, DNA extraction, and CTNNB1 gene exon-3 sequencing.

Of the 37 cases of SPTP studied, 36 were female, and one was male. Most tumors of variable sizes occurred in the pancreatic head or tail (78.4%). Immunohistochemical studies always revealed β-catenin expression and pathological analysis confirmed lymph node invasion. CTNNB1 gene sequencing showed mutations in 34 of 37 tumors (91.9%), exclusively affecting codons 32, 33, 34, and 37.

The results show clinical and immunohistochemical associations with pancreatic tumor location, tissue invasion, and specific gene mutations. These findings highlight the prevalence of CTNNB1 mutations in SPTP and underscore the significance of examining population diversity in rare tumor research to determine the likelihood of clinical and molecular correlations for personalized treatment.

Immune checkpoint inhibitors are used in a wide range of cancers, offering durable responses for a substantial subset of patients. However, immune-related adverse events, the most clinically consequential checkpoint inhibitor-associated adverse reactions, pose a key challenge in practice, affecting virtually any organ system, resulting in treatment interruption, morbidity, or mortality. Patient education, early recognition, and effective management are essential to limit complications and maintain continuity of immunotherapy. Achieving this requires well-informed multidisciplinary teams who can identify, evaluate, and manage immune-related adverse events promptly. This review summarizes the most clinically significant immune-related adverse events and highlights the key principles of multidisciplinary diagnosis and management most relevant to the practicing allergist-immunologist to optimize patient outcomes.

Perineural invasion (PNI) is a hallmark of malignancy in solid tumors, including oral squamous cell carcinoma (OSCC), and is closely associated with poor prognosis. Emerging evidence suggests a critical association between PNI and the tumor immune microenvironment (TME).

In this study, we used spatial transcriptomics, in vitro and in vivo experiments, and clinical specimen validation to systematically study the interplay between neural infiltration and immune modulation in OSCC.

Our results suggest that intratumoral nerves may enhance the recruitment of regulatory T cells (Tregs) through C-C motif chemokine ligand 5 (CCL5)-mediated chemotaxis and further promote the acquisition of an immunosuppressive phenotype in Tregs by activating the RAMP1 signaling pathway. Through these coordinated mechanisms, neural components in the TME contribute to immune suppression and facilitate tumor progression. Therapeutically, both combination of CCL5 blockade with anti-CTLA-4 antibody and the combination of RAMP1 blockade with anti-PD-1 antibody exhibited significantly enhanced anti-tumor efficacy.

This study highlights a previously underappreciated neural-Treg axis in the TME and provides new insights into potential combinatorial strategies for cancer immunotherapy.

Renal carcinoma remains a highly lethal malignancy, and tumor vaccine efficacy is frequently hampered by a profoundly immunosuppressive tumor microenvironment. V-domain Ig suppressor of T-cell activation (VISTA), an inhibitory immune checkpoint enriched in myeloid cells and regulatory T cells (Tregs), represents a critical barrier to effective antitumor immunity. Targeting VISTA may therefore provide a promising strategy to overcome immune suppression and enhance tumor vaccine efficacy.

Recombinant adenoviral vaccines encoding carbonic anhydrase IX (CAIX) and VISTA (Ad-CAIX and Ad-VISTA) were constructed and validated for efficient antigen expression. The antitumor efficacy of Ad-VISTA/CAIX co-immunization was evaluated in subcutaneous, lung metastatic, orthotopic, and anti-programmed cell death protein 1-resistant renal carcinoma models. Vaccine-induced immune responses were assessed by flow cytometry, immunohistochemistry, ELISA, cell proliferation assays, cytotoxic T lymphocyte (CTL) assays, and in vivo immune cell depletion experiments.

Ad-VISTA immunization markedly potentiated the therapeutic efficacy of CAIX-targeted vaccination, resulting in significant tumor growth inhibition and prolonged survival across multiple renal carcinoma models. Mechanistically, VISTA-targeting remodeled the tumor microenvironment by enhancing the infiltration and activation of dendritic cells (DCs) and CD8⁺ T cells while reducing immunosuppressive myeloid cells and Tregs. Ad-VISTA/CAIX co-immunization promoted the expansion and maturation of multiple DC subsets, characterized by increased expression of CD40, CD80, CD86, and major histocompatibility complex molecules, thereby facilitating efficient antigen presentation. VISTA immunization elicited robust antigen-specific antibody and neutralizing responses, restored CD8⁺ T-cell proliferation, and enhanced CTL-mediated tumor cell killing. Depletion of CD8⁺ T cells abrogated therapeutic efficacy of Ad-VISTA/CAIX vaccine, establishing its essential role in tumor control. Furthermore, combined vaccination induced durable memory CD8⁺ T-cell responses capable of preventing tumor recurrence on rechallenge.

These results indicated that vaccine-induced VISTA blockade effectively amplifies DC-mediated CD8⁺ T-cell immunity and synergistically enhances tumor vaccine efficacy. Targeting VISTA represents a promising immunotherapeutic strategy for improving vaccine-based treatments in renal carcinoma.

NKG2A is a C-type lectin that heterodimerizes with CD94 creating an inhibitory immunoreceptor. S095029 is a fully human monoclonal IgG1 anti-NKG2A antibody with attenuated Fc-effector functions that specifically binds the NKG2A/CD94 heterodimer, blocking the interaction with its ligand HLA-E. Sym021 is an anti-programmed cell death protein 1 (PD-1) IgG1 antibody. Preclinical data demonstrated that S095029 combined with Sym021 increases antitumor activity.

This first-in-human, open-label, multicenter study (NCT05162755) evaluated safety, tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamics (PD) of S095029 as monotherapy or in combination with Sym021 in patients with advanced solid tumors. Monotherapy regimen included two doses of S095029 every 2 weeks (Q2W) followed by single-agent Sym021 (Q2W). Adverse events were defined per Common Terminology Criteria for Adverse Events V.5.0. Antitumor activity was evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Cytokine secretion as PD markers and target engagement/receptor occupancy were assessed in peripheral blood. Selected immune markers were assessed by multiplex immunofluorescence on tumor biopsies.

As of July 25, 2025, 21 patients with heavily pretreated solid tumors were treated with S095029 as a single agent (10, 30, 100, 300, 750 and 1,500 mg) and 20 patients were treated with S095029 (30, 100, 300, 750 and 1,500 mg) in combination with Sym021 (200 mg). S095029 was well tolerated without dose-limiting toxicities for both monotherapy and combination with anti-PD-1. A maximum tolerated dose was not reached. Two patients (9.5%; uterine sarcoma, porocarcinoma) who received one cycle of S095029 monotherapy followed by Sym021 and two patients (10%; leiomyosarcoma, squamous cell carcinoma of unknown primary) who received S095029 in combination with Sym021 showed confirmed partial responses. None of these patients had received prior anti-PD-1 treatment. The clinical benefit rate (complete response+partial response+stable disease ≥6 months) by RECIST V.1.1 in all enrolled patients was 19.5%. S095029 serum concentrations increased with dose for both monotherapy and combination with Sym021. Full receptor occupancy was achieved starting at 30 mg Q2W. Increases in levels of monokine induced by gamma interferon, macrophage inflammatory protein 1-beta and tumor necrosis factor-α in peripheral blood were detected following treatment with S095029+Sym021 suggesting immune cell activation on treatment.

The anti-NKG2A antibody S095029 in combination with anti-PD-1 Sym021 demonstrated a favorable safety profile and exhibited signal of antitumor activity in unselected, heavily pretreated patients with advanced malignancies.

NCT05162755.

Prostate-specific membrane antigen (PSMA)-based vaccination represents a promising immunotherapeutic strategy for prostate cancer; however, its efficacy remains constrained by tumor-induced immune evasion and insufficient activation of antigen-presenting cells. Galectin-9 (LGALS9), an immunoregulatory lectin that contributes to immune suppression, is therefore an attractive target for overcoming tumor-induced immune tolerance.

Recombinant adenoviral vaccines encoding PSMA and LGALS9 (Ad-PSMA and Ad-LGALS9) were generated and validated for antigen expression in vitro and in vivo. Therapeutic efficacy was evaluated in murine subcutaneous, bone metastatic, and humanized prostate cancer models. Vaccine-induced immune responses were characterized by flow cytometry, ELISA, enzyme-linked immunospot (ELISpot), immunohistochemistry, EdU proliferation assays, cytotoxic T lymphocyte assays, and cell depletion experiments.

Pre-immunization with Ad-LGALS9 significantly potentiated the therapeutic efficacy of the Ad-PSMA vaccine in subcutaneous, bone metastatic, and humanized prostate cancer models, resulting in pronounced tumor growth inhibition and prolonged survival. Mechanistically, LGALS9 targeting enhanced dendritic cell (DC) activation and maturation, upregulating CD80, CD86, major histocompatibility complex-II, and CD40 expression and promoting efficient antigen cross-presentation. This facilitated robust priming and expansion of multifunctional CD8⁺ T cells producing interferon-γ, interleukin-2, and tumor necrosis factor-α, which mediated potent cytotoxicity against PSMA-expressing tumor cells. Furthermore, LGALS9 immunization induced high-titer neutralizing antibodies that disrupted the LGALS9/TIM-3 inhibitory axis, alleviating T-cell exhaustion. Combined Ad-LGALS9/PSMA vaccination established durable memory CD8⁺ T-cell responses that conferred protection against tumor rechallenge.

Targeting LGALS9 enhances DC-mediated CD8⁺ T-cell immunity and synergistically augments the therapeutic efficacy of tumor vaccines, representing a promising immunotherapeutic strategy for prostate cancer.

Pancreatic cancer remains among the deadliest malignancies, with a 5-year survival of ~13%. Chimeric antigen receptor (CAR) T -cell therapy offers hope, but conventional αβ T cells can trigger severe toxicities, including graft-versus-host disease (GvHD) when used for allogeneic therapy. By contrast, γδ T cells recognize tumors without MHCmajor histocompatibility complex restriction and are unlikely to cause GvHD, making them attractive candidates for "off-the-shelf" immunotherapy. Li et al engineered the Vδ1 subset of γδ T cells with a CAR targeting prostate stem cell antigen (PSCA) and compared these cells to CAR-engineered Vδ2 γδ and conventional αβ T cells in preclinical pancreatic cancer models. All three groups showed comparable tumor killing efficacy, but the CAR Vδ1 T cells induced none of the GvHD or systemic toxicity seen with CAR αβ T cells. They also displayed lower exhaustion than CAR Vδ2 cells, suggesting potential for greater persistence. Vδ1 CAR T cells could be expanded robustly ex vivo and remained highly potent even after cryopreservation, a key "off-the-shelf" requirement. These findings position CAR Vδ1 T cells as a safer alternative to traditional CAR T cells. Future rigorous clinical evaluation will be needed to confirm superior safety and efficacy of this promising approach in patients.