Abstract Background: Over two dozen histological types of salivary gland cancers are recognized comprising 3-5% of all head and neck cancers. Response to chemotherapy and actionable target expression in patients with metastatic disease vary by histological type e.g. HER2 and/or androgen receptor are often overexpressed by salivary duct carcinomas and NTRK fusions often present in secretory carcinomas. Overall results of this phase II basket trial have been previously reported (Gupta 2025). Herein we report additional data from the metastatic salivary gland cohort by histological subtype. Methods: IND.228 was a prospective multi-center, non-blinded, open-label phase II basket trial that enrolled 8 cohorts of patients with rare cancers including a salivary gland cohort. Eligible patients had incurable disease with no known life-prolonging treatment options or contraindications to immunotherapy and ECOG performance status 0 or 1. Tumor PD-L1 expression was not required and patients with adenoid cystic carcinoma were excluded. Patients received durvalumab 1500 mg IV plus tremelimumab 75 mg IV q4 weeks for 4 cycles followed by durvalumab q4 weeks until disease progression. The primary outcome was objective response by RECIST 1.1 criteria. Results: 21 patients with incurable salivary gland cancer were enrolled. Of 20 patients evaluable for response there were 6 females and 14 males, median age 61 years (range, 40-72) with a median of 3 metastatic sites (range, 1-5). Histological types were salivary duct carcinoma (8), acinic cell carcinoma (5), adenocarcinoma (3), clear cell carcinoma (2), and others (2). All had diagnosis confirmed by central pathology review. 190 cycles of treatment were given with a median of 7 cycles per patient (range, 1-40). Four patients had partial responses, 8 had stable disease, and 8 had progressive disease as best response. The proportions of response and response plus stable disease by histological type, respectively, were salivary duct carcinoma (2/8, 4/8), acinic cell carcinoma (1/5, 4/5), and adenocarcinoma (1/3, 3/3). 10/13 patients with avaialable tumor grade had high-grade cancers. Progression-free survival ranged from 7.3-59.3+ months in responding patients, and from 3.8-11.4 months in stable disease patients. One patient with salivary duct carcinoma received 40 cycles of treatment and had a response duration of over 5 years. Conclusions: Patients with salivary duct carcinoma, acinic cell carcinoma, and adenocarcinoma appeared to benefit from combined CTLA-4 and PD-L1 immune checkpoint blockade. Immune checkpoint blockade deserves further study and consideration as a treatment option in these histological types of incurable salivary gland cancer. Citation Format: Eric Winquist, John Hilton, Christian Kollmannsberger, Danielle Charpentier, Dorie-Anna Dueck, Hal Hirte, Sebastien Hotte, Rahima Jamal, Raymond Jang, Andrew Maksymiuk, Randeep Sangha, Stephanie Snow, Osama Souied, Jennifer Spratlin, Ralph Wong, Abha Gupta, Thierry Alcindor, Quincy Chu, Derek Jonker, Torsten Nielsen, Ming Tsao, Tricia Cottrell, Joana Sederias, Siwei Zhang, Wei Tu, Janet Dancey. Durvalumab and tremelimumab in patients with metastatic non-adenoid cystic salivary gland cancer treated in the CCTG IND.228 phase II basket trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A029.

Assessment of the tumor immune microenvironment can be used as a prognostic tool for improved survival and as a predictive biomarker for treatment benefit, particularly from immune modulating treatments including cytotoxic chemotherapy.Using Digital Spatial Profiling (DSP), we studied the tumor immune microenvironment of 522 breast cancer cases by quantifying 35 immune biomarkers on tissue microarrays from the MA.5 phase III clinical trial. In this trial, node-positive breast cancer patients were randomized to receive either a non-anthracycline chemotherapy (CMF) or anthracycline-containing cytotoxic chemotherapy (CEF). Donor block hematoxylin and eosin (H&E)-stained sections were scored for the level of stromal tumor infiltrating lymphocytes (sTILs), according to the international guidelines. We hypothesized that patients with higher levels of tumor immune infiltration, assessed by either DSP or H&E staining, would benefit from CEF (relative to CMF) more than patients with lower immune infiltration.Unsupervised hierarchical clustering of digitally scored biomarkers revealed two patient clusters: immune infiltrated vs. ignored. Following a pre-specified statistical plan crafted to meet ReMARK guidelines, we found that the DSP-derived Immune Cluster assignment did not predict an improved 10-year relapse-free survival for patients receiving CEF compared to CMF. However, a secondary hypothesis revealed a significant predictive value for H&E-sTILs assessed on full-faced sections for CEF benefit over CMF in the entire cohort and the HER2-enriched subset. As exploratory analyses, supervised clustering of DSP scored biomarkers suggested that low levels of TIM-3 and high levels of HLA-DR and PD-L1 are associated with sensitivity to CEF.Although novel high-plex techniques provide a detailed insight into the tumor microenvironment, conventional H&E staining remains a powerful tool that can be applied onto full-faced sections to assess the value of immune microenvironment, particularly sTILs, in predicting benefits from immunogenic chemotherapies.

Supplementary Figure S1 shows the expression of the 50 genes in the PAM50 signature, obtained from the 164-gene codeset.

Supplementary Figure S2 shows a forest plot comparing basal vs. non-basal subtype as defined by PAM50 or by IHC, and their associations with disease free survival on capecitabine vs. observation arm.

Synovial sarcoma is an aggressive cancer generally affecting adolescents and young adults and is characterized by high rates of recurrence and metastasis. It is primarily driven by the fusion oncoprotein SS18::SSX, the product of a pathognomonic chromosomal translocation t(X;18), which facilitates widespread epigenetic dysregulation through interactions with complexes, such as the BRG1/BRM-associated factor complex and polycomb repressive complexes. Previous attempts to perform mass spectrometry (MS) of the SS18::SSX interactome have been limited by the lack of an antibody to detect the endogenous protein, hence relying on single-cell lines with exogenous tags. We previously used a monoclonal antibody, which specifically detects SS18::SSX containing the canonical fusion junction (seen in 95% of cases) and established its utility in several applications. Using that antibody, MS analysis revealed that the SS18::SSX protein undergoes alternative splicing of exon 8 in SS18. We next performed immunoprecipitation MS of SS18::SSX in 6 immortalized human synovial sarcoma cell lines and identified the canonical polycomb repressive complex member chromobox 4 (CBX4), as a novel interactor of the oncoprotein. Immunohistochemical staining of several epigenetic factors on a human synovial sarcoma tissue microarray showed an association of synovial sarcoma samples with higher CBX4 expression. Last, an analysis of CBX4 expression across 337 samples from 12 sarcoma subtypes, carcinomas, and normal tissue demonstrates higher expression in synovial sarcoma samples compared with other tissue types. These results highlight a crucial approach in identifying important partners of SS18::SSX in synovial sarcoma to establish new biological pathways that contribute to the disease.

Supplementary Table S1 shows the gene list for the NanoString custom nCounter codeset included in the study. Supplementary Table S2 shows patient characteristics in the GEICAM/CIBOMA translational study cohort versus the original trial. Supplementary Table S3 shows the distribution of PAM50 intrinsic subtypes in the GEICAM/CIBOMA translational study cohort. Supplementary Table S4 shows the differential gene expression analysis performed on the 164 genes included in the custom codeset comparing PAM50 non-basal vs. basal-like subtype and their biological processes. Supplementary Table S5 shows multivariate survival analysis and interaction tests for the four genes and metagenes included in the prespecified hypotheses testing their association with DFS. Supplementary Table S6 shows multivariate survival analysis and interaction tests for the continuous expression of the 38 individual genes included in the prespecified hypotheses testing their association with DRFS. Supplementary Table S7 shows multivariate survival analysis and interaction tests for the continuous expression of the 38 individual genes included in the prespecified hypotheses testing their association with OS. Supplementary Table S8 shows multivariate survival analysis and interaction tests for the continuous expression of the 38 individual genes included in the prespecified hypotheses testing their association with DFS. Supplementary Table S9 shows multivariate survival analysis and interaction tests restricted to the PAM50 non-basal subgroup. Supplementary Table S10 shows Exploratory analysis for the prognostic capacity of the continuous expression of genes and metagenes restricted to the PAM50 non-basal subgroup.

The SS18::SSX oncogene is the driver of synovial sarcoma, an aggressive cancer presenting in young adults that has poor long-term outcomes. Over the past five years, significant progress has been made in understanding the molecular, genomic, and epigenetic mechanisms underlying synovial sarcoma. This review synthesizes recent advancements in synovial sarcoma, including diagnostic pathology, genomic profiling, SS18::SSX biology, epigenetic dysregulation, proteomics, targetable pathways and immunotherapy. Key findings include the identification of rare but instructive alternative gene fusions, the roles of PRC1 and of liquid-liquid phase separation in SS18::SSX-mediated oncogenesis, and the development of epigenetic and engineered T-cell therapies. These advances offer new hope for improved treatments and outcomes in synovial sarcoma patients, though challenges remain in overcoming resistance and ensuring equitable access to emerging therapies.

Supplementary Figure S3 shows a forest plot of the exploratory categorical analysis of selected (meta)gene expression and their association with distant recurrence free survival on the capecitabine arm vs. observation.

NCIC-CTG MA.5 and DBCG 89D are symmetrically designed randomized trials comparing adjuvant cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in high-risk breast cancer patients. In a joint analysis we evaluate the predictive value in terms of anthracycline benefit of molecular subtyping by PAM50. A statistically significant interaction (P = 0.008) between continuous Risk of Recurrence (ROR) score and treatment regimen is evident, translating into a clear distinct treatment effect according to ROR score category with HR 0.51 for ROR score ≥ 72 and HR 1.10 for ROR score < 52 (Pinteraction = 0.004). The analysis provides evidence of the benefit from anthracycline in HER2-enriched subtype; for patients with discordance of HER2 subtype and clinical HER2 status, HER2-enriched subtype was predictive of anthracycline benefit whereas clinical HER2 positive status was not. Anthracycline-based adjuvant chemotherapy may safely be withheld for patients with a low ROR score while the benefit increases with increasing ROR score.

Supplementary Data S1 shows exploratory analysis for the predictive capacity of the continuous expression of additional genes and metagenes included in the codeset. Supplementary Data S2 shows exploratory analysis for the prognostic capacity of the continuous expression of the selected genes and metagenes

Background Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L 1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab (TM) in parallel cohorts of patients with carefully selected rare cancer types in which these agents had not previously been evaluated in phase II trials and for which there was clinical or biological rationale for dual immune checkpoint inhibitor therapy to be active. Methods We designed a multi-centre, non-blinded, open-label phase II basket trial with each of the following 8 rare cancers considered a separate phase II trial: salivary carcinoma, carcinoma of unknown primary (CUP) with tumour infiltrating lymphocytes and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary (CCCO) or squamous cell carcinoma of the anal canal (SCCA). The primary objective was to evaluate the response rate of the combination of D and TM, and the secondary objectives were to evaluate the tolerability and safety of D and TM combination. Eligible patients had advanced, metastatic or recurrent, or unresectable cancer with no known life-prolonging treatment option, age >= 16 years, ECOG performance status 0 or 1. Patients received D (1500 mg IV) + TM (75 mg IV) on Day 1 q4 weeks for 4 cycles followed by D q4 weeks until disease progression. This trial is registered with ClinicalTrials.gov, NCT02879162. Findings From December 14th, 2016, to August 14, 2019, 140 patients enrolled into seven cohorts. The rare melanoma cohorts were closed due to lack of accrual. Of the 140 patients enrolled, 138 were eligible, 138 were evaluable for toxicity and 128 (91%) were evaluable for response. Durable responses were noted in all cohorts except for osteosarcoma. The overall response rate for eligible patients was 16% (95% CI: 10-23%). The response rates in each cancer cohort were undifferentiated pleomorphic sarcoma 15% (n = 3/20; 95% CI 3-38%), salivary carcinoma 20% (n = 4/20; 95% CI: 6-44%), CUP 17% (n = 3/18; 95% CI 4-41%), SCCA 10% (n = 2/20; 95% CI 12-32%) and CCCO 21% (n = 8/39; 95% CI 9-37%). Grade 3/4 adverse events were rare, where 4 patients experienced grade 4 related events and39 patients experienced grade 3 events. Interpretation Durvalumab + tremelimumab treatment resulted in meaningful responses in salivary carcinoma and CCCO and deserves further exploration in front-line studies.

Immunotherapy has emerged as a new treatment modality in some soft tissue sarcomas, particularly for tumors associated with tertiary lymphoid structures (TLS). These structures are functional lymphoid aggregates, and their presence is indicative of an active anticancer immune response in the tumor microenvironment. The assessment of TLS as a predictive biomarker at scale on patient specimens remains challenging. While tissue microarrays could facilitate this assessment, it is unclear whether small microarray cores can represent and identify associated TLS responses.We sought to use multiplex immunohistochemistry to identify key components of TLS: T cells, B cells, and dendritic cells. The multiplex panels (CD3, CD20, CD208 and PNAd) were applied onto 80 cases both on tissue microarrays and on their cognate available full-faced sections from epithelioid sarcoma and dedifferentiated/well-differentiated liposarcoma case series. Tissue microarrays were digitally scored for the number of immune cells using the HALO image analysis platform, and cognate full-faced sections were visually evaluated for the presence of TLS. An independent validation set of soft tissue sarcomas (N=49) was stained with the CD3, CD20, and CD208, and scored by QuPath.A Combined Immune Marker (defined as the presence of more than more than 24% CD3+T cell, or 0.51% CD20+B cell, or more than 0.14% CD208+mature dendritic cell on tissue microarray core) is highly specific (100%) and moderately sensitive (61%) to predict the existence of TLS on full-faced sections. The Combined Immune Marker showed a sensitivity of 25% and specificity of 91% on the validation set.The Combined Immune Marker assessed on tissue microarrays is highly specific to infer the presence of TLS present on cognate full-faced sections. Therefore, despite the small area sampled, tissue microarrays may be utilized to assess the clinical value of TLS on datasets where specificity is critical and large sample size can mitigate low to moderate sensitivity.

Heterogeneity in chromatin states defines a disease spectrum in synovial sarcoma Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18-SSX fusion oncoprotein. Previous research has indicated that SS18-SSX interacts with BAF, a chromatin remodeling complex, thereby suggesting that the deregulation of chromatin architecture serves as the oncogenic driver in this tumor type. In this study, we conducted a comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumors, employing RNA-seq, whole-genome sequencing (WGS), whole-genome bisulfite sequencing (WGBS), and chromatin immunoprecipitation sequencing (ChIP-seq) for eight histone modifications. Our epigenomic analysis unveiled distinct subgroups defined by enhancer activity and an anomalous association between the repressive H2AK119Ub and H3K27me3 marks. Furthermore, we observed a remarkable level of epigenetic state heterogeneity at fusion target genes. Notably, we discovered that the presence of bivalent promoters, marked simultaneously by the repressive H3K27me3 and the activating H3K4me3 modifications, holds significant prognostic value, surpassing the predictive capacity of tumor grade in determining patient outcomes. Lastly, our investigation identified unique epigenetic characteristics specific to SyS, such as an expansion of the H3K4me3 mark, which correlates with pronounced DNA hypomethylation of promoter regions.

Summary Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. To examine the epigenomic state of SyS we performed comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumours. Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. We identify cell-of-origin signatures defined by enhancer states and reveal unexpected relationships between H2AK119Ub1 and active marks. The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype. We explore these distinctive features as potential vulnerabilities in SyS and identify H3K4me3 inhibition as a promising therapeutic strategy.

For more than a century, microscopic histology has been the cornerstone for cancer diagnosis, and breast carcinoma is no exception. In recent years, clinical biomarkers, gene expression profiles, and other molecular tests have shown increasing utility for identifying the key biological features that guide prognosis and treatment of breast cancer. Indeed, the most common histologic pattern-invasive ductal carcinoma of no special type-provides relatively little guidance to management beyond triggering grading, biomarker testing, and clinical staging. However, many less common histologic patterns can be recognized by trained pathologists, which in many cases can be linked to characteristic biomarker and gene expression patterns, underlying mutations, prognosis, and therapy. Herein we describe more than a dozen such histomorphologic subtypes (including lobular, metaplastic, salivary analog, and several good prognosis special types of breast cancer) in the context of their molecular and clinical features.

Importance:The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective:To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants:Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure:TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures:The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results:This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance:In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

Summary Synovial sarcoma is an aggressive soft-tissue malignancy that is characterized by a pathognomonic t(X;18)(p11.2;q11.2) translocation, which produces the fusion oncogene named SS18::SSX . Despite recent advancements in our understanding of synovial sarcoma biology, the cell-of-origin remains undefined. A mesenchymal stromal cell (MSC) specific CreERT2 line was employed to express SS18::SSX in fibroblasts and related cell types, resulting in 100% penetrant synovial sarcoma development in mice, with a median latency period of 16.2 ± 2.5 weeks. Murine tumours exhibited high concordance with human synovial sarcoma sub-types at the histological and molecular levels 1 . Genetic refinement of the cell-of-origin revealed that synovial sarcomas derive from a rare Hic1 + Pdgfra + Lgr5 + fibroblastic population. Furthermore, longitudinal multi-omic profiling along the transformation continuum revealed the step-wise acquisition of a transformed phenotype initiated by the loss of a mature fibroblastic profile and subsequently, the gradual unmasking of an epigenetically embedded embryonic MSC program. Adult and embryonic MSCs exhibited overlapping H2AK119ub and H3K4me3/H3K27me3 (bivalent) histone marks, while SS18::SSX-mediated transformation culminated in the widespread loss of H3K27me3 at these genes and their consequent transcription. Collectively, these studies define a rare MSC context, conducive for SS18::SSX-mediated transformation, and demonstrate that SS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype.

SUMMARY Synovial sarcoma (SyS) is driven by the expression of a chromosomal translocation-generated SS18::SSX fusion oncoprotein 1,2 . This oncoprotein fuses the SSX carboxy terminal tail that binds ubiquitylated histone H2A (H2AK119ub) 3–6 to the SS18 component of both canonical (CBAF) and non-canonical (GBAF, GLTSCR1-containing) BAF-family chromatin remodeling complexes 7–11 , wherein SS18::SSX reprograms the epigenetic landscape. Mice that express SS18::SSX develop tumors that faithfully recapitulate human SyS histopathologically and molecularly 12–14 , allowing dissection of transcriptional reprogramming in vivo 15,16 . Here, we show that SS18::SSX redistributes GBAF complexes broadly to promoters and distal enhancers decorated by H2AK119ub, which uncharacteristically lack the transcription-silencing trimethylation of H3K27 that otherwise accompanies H2AK119ub. Fusion-GBAF instead associates with H2AK119ub and transcription-enabling H3K4 trimethylation (promoters), monomethylation (distal enhancers), and H3K27 acetylation (both). CBAF with the fusion redistributes away from typical loci, avoids H2AK119ub-bearing regions, and instead narrowly flanks transcription start sites (TSSs), co-distributed with polybromo BAF (PBAF). Accelerated tumorigenesis in our SyS mouse model followed deletion of Smarcb1 (PBAF and CBAF), Pbrm1 (PBAF-specific), and Arid1a or Arid1b (CBAF-specific). While tumors lacking Arid1a or Arid1b retained SyS character, loss of Smarcb1 or Pbrm1 resulted in tumors lacking SyS features. These findings suggest that SyS transcriptional reprogramming includes both improper GBAF localization and gene activation at H2AK119ub-bearing regulatory regions and improper gene silencing through loss of CBAF.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.