B cells and their cellular neighborhoods, i.e., lymphoid aggregates (LAs) and tertiary lymphoid structures (TLS), have not been extensively studied in melanoma brain metastases (BM) or lung adenocarcinoma (LUAD) BM, despite their prognostic value and role in immunotherapeutic responses. In this study, we evaluated the prognostic benefit and heterogeneity of B cell infiltration and LA formation in more than 200 patients with melanoma-BM or LUAD-BM. We found that LAs were associated with increased intratumoral CD8+T cells in melanoma-BM compared with LUAD-BM. Moreover, the presence of LAs was associated with an increased survival benefit in patients with melanoma-BM but not in those with LUAD-BM. Despite lacking canonical TLS hallmarks, LAs in BM contained proliferating B and T cells with the potential for effector function. Our work has solidified the need for the mechanistic investigation of intracranial B cells and the immune neighborhoods in which they reside.
Cancer cachexia is a devastating wasting syndrome with no approved therapies. In this study, we identify the tumor-derived glycoprotein ADAMTSL4 as a circulating factor associated with body weight loss in preclinical cachexia models and patients with colorectal and lung cancers. In mice, Adamtsl4 overexpression converted non-cachexia-inducing tumors into cachexia-inducing tumors, whereas its deletion in cachexia-inducing tumors spared fat and muscle, blunted muscle atrophy signatures, and reduced cachexia severity. ADAMTSL4 engages the latency-associated peptide (LAP) of TGFβ1, promoting local activation of TGFβ1 at muscle cell membranes. Genetic blockade of proTGFβ1 or pharmacologic inhibition of TGFβ signaling reduced ADAMTSL4-dependent wasting in adipocytes and muscle cells. Suppression of tumor-derived ADAMTSL4 attenuated skeletal muscle fibrosis in mice. Together, the association between increased circulating ADAMTSL4 levels and TGFβ-driven muscle atrophy and fibrosis gene signatures in patients with cachectic cancer identifies ADAMTSL4 as an upstream regulator of TGFβ1 and a potential therapeutic target in cancer cachexia. SIGNIFICANCE:Cancer cachexia lacks effective therapies and remains a major cause of cancer-related morbidity and mortality. We identify tumor-derived ADAMTSL4 as an upstream regulator of latent TGFβ activation via LAP engagement that promotes multiorgan wasting and fibrosis-related remodeling. Targeting ADAMTSL4 may provide a selective therapeutic strategy without systemic TGFβ pathway blockade.
Breast and prostate cancers share notable similarities in their progression to invasive disease, providing a unique opportunity to uncover common mechanisms of malignant transition. By integrating volumetric reconstruction with multimodal spatial profiling, Storrs and colleagues revealed the precancer-to-cancer transition as a continuous three-dimensional process and identified shared molecular programs associated with invasion. See related article by Storrs et al., p. 1819.
Zhou and colleagues identify mitochondrial complex I activity, mediated through NDUFA9, as a critical determinant of natural killer (NK) cell metabolic fitness and antitumor function in glioblastoma. Their study links impaired oxidative phosphorylation to glutamine dependence, epigenetic repression of effector programs, and loss of NK cell activity, highlighting mitochondrial fitness as an actionable axis for improving cellular immunotherapy in solid tumors. See related article by Zhou et al., p. 1924.
We provide an overview of a recent study in Cancer Discovery by Leongamornlert and colleagues involving genomic profiling of 30 patients with myeloproliferative neoplasms using available blood or bone marrow samples to assess what factors underlie disease evolution or predict stability. See related article by Leongamornlert et al., p. 1843.
Messenger RNA (mRNA) cancer vaccines have progressed rapidly, with personalized platforms such as mRNA-4157 and BNT122 demonstrating feasibility, safety, and durable immune activity but limited scalability. Off-the-shelf constructs, including BNT111 and BNT113, enable faster, broader deployment, yet they risk reduced precision or immune tolerance. These complementary approaches reveal key translational dualities: personalization versus shared antigen (off-the-shelf), potency versus safety, and speed versus durability. This mini-review synthesizes emerging clinical evidence and outlines strategies such as modular vaccine design, prime-boost vaccination regimens, and adaptive trial frameworks to reconcile these trade-offs and advance scalable, durable mRNA vaccines for broad oncologic impact. SIGNIFICANCE:By dissecting the competing design pressures that shape mRNA vaccine performance, this mini-review proposes integrative strategies, spanning modular architectures, prime-boost regimens, and adaptive trials, to reconcile immunologic potency with manufacturability and safety, charting a roadmap toward next-generation cancer vaccines.
Across cancer, one of the most frequent examples of histologic transformation is the evolution of follicular lymphoma (FL) to an aggressive large cell lymphoma. Despite recent progress, understanding of the molecular and cellular underpinnings of transformation remains incomplete. Here, we dissect the interplay of tumor and microenvironment cell populations across transformation through a multimodal investigation of 95 FL and transformed FL (tFL) samples, including single-cell and bulk RNA-sequencing alongside spatial transcriptomics and proteomics, and validate findings across independent FL-tFL pairs. Upon transformation, fibroblasts and GPNMB+ macrophages increase while lymph-node organizing follicular dendritic and CCL21+ fibroblastic reticular cells were lost, resulting in an altered spatial distribution of cytokines that impacts T cell infiltration and macrophage differentiation and function. Secreted stromal and macrophage signals were further evident by non-invasive plasma proteomics. Taken together, our data reveal expansion of macrophages and fibroblasts as key features of transformation with potential diagnostic and therapeutic implications.
Beyond established rare fusions, such as ALK and ROS1, emerging ultrarare fusions involving receptor tyrosine kinases or their ligands, including EGFR-SHC1, further guide us to uncover novel mechanisms of oncogenic activation and corresponding treatment strategies. Collectively, rare and ultrarare genomic events are driving precision oncology toward an increasingly individualized era of "ultraprecision" cancer therapy. See related article by Zheng et al., p. 1573.
Ever since immune checkpoint blockade showed activity in the treatment of cancer, the search has been on for combination regimens that make this therapy more effective. In this issue, Blagg and colleagues describe an unorthodox approach to increasing the effectiveness of cancer immunotherapy. See related article by Blagg et al., p. 1649.
Brady and colleagues investigated the mutational consequences of cancer treatment on the genomes of 160 childhood cancer survivors who developed a subsequent neoplasm (SN). Their research aids in directing the next steps toward the prevention of SNs. See related article by Brady et al., p. 1590.
Combination therapies involving vascular targeting drugs have shown promise in overcoming resistance to immunotherapy. However, the prerequisite for vascular modulation to evoke an effective antitumor T-cell response remains elusive. Tracing the transcriptional response of liver metastasis-associated peritumoral and tumor endothelial cells (TEC) to T-cell intervention, we discovered an immunomodulatory TEC subpopulation that highly expressed lipoprotein lipase (LPL). LPL+ TECs facilitated intratumoral homing of activated antitumor CD8+ T cells driving liver metastatic regression. Mechanistically, LPL enhanced MHC-I-dependent cross-presentation of tumor antigens on TECs for T-cell trafficking. Consequently, LPL+ TECs were recognized and targeted by T cells, further aiding antitumor response. Corresponding analyses of human liver metastasis samples identified a significant correlation between the presence of intratumoral LPL+ blood vessels and the accumulation of T cells. Altogether, the study identifies a decisive role of TECs in orchestrating an effective T-cell response by overcoming tumor's intrinsic insufficient antigen presentation. SIGNIFICANCE:The study identifies LPL+ TECs as orchestrators of activated CD8+ T-cell homing into immunologically cold tumors with low baseline MHC-I expression. Enhancing tumor antigen exposure by MHC-I cross-presentation in TECs presents a promising approach to compensate the intrinsic inability of tumor cells and boost antitumor immunotherapy.
Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions over a decade-plus, offering a window for interception in high-risk individuals, but current surveillance detects a minority of precursors. Mutant KRAS (mKRAS) is present in most PDACs and their precursors, making it an appealing target for immune-based interception. We conducted a phase I, first-in-human study of a peptide vaccine targeting six common KRAS mutations (mKRAS-VAX) in 20 individuals with hereditary PDAC predisposition and a radiographic pancreatic abnormality (NCT05013216) to assess safety, immunogenicity, and T cell persistence. Adverse events were grade 1-2. Vaccination elicited a significant mKRAS-specific T cell response in 18/20 participants (90%). Longitudinal TCR sequencing demonstrated persistence of vaccine-induced mKRAS-specific clonotypes for up to 2 years. Over a median follow-up of 16.5 months, no participants developed PDAC. These findings demonstrate that mKRAS-VAX is safe and generates durable T cell responses, which support the advancement of mKRAS-targeted vaccination for PDAC interception.
Ewing sarcoma is characterized by a chromosomal translocation resulting in the fusion protein EWSR1::FLI1. We utilize endogenous EWSR1::FLI1 target gene reporters in patient-derived cell lines to perform a high-throughput phenotypic screen to identify small molecules that impair the EWSR1::FLI1 transcriptional program. We discovered that inhibitors of cyclin-dependent kinase 8 (CDK8), including a novel pyridyl imidazole, altered transcription of EWSR1::FLI1 target genes and CDK8 co-localized with EWSR1::FLI1 preferentially on single GGAA DNA binding motifs. Using pooled CRISPR screening, biochemical studies, and chromatin profiling, we discovered that CDK8 inhibitors suppressed proliferation of Ewing sarcoma cells through a gain-of-function mechanism by inducing molecular trapping of the CDK8 kinase module and Mediator complex on chromatin. This mechanism has implications for the development of small molecules to target transcription and suggests that impairment of transcriptional regulatory complex dynamics might serve as a vulnerability in cancers in which the dominant oncogenes act as dosage-sensitive transcription factors.
Alveolar rhabdomyosarcoma (aRMS) is a fusion-driven pediatric cancer with poor survival and limited therapeutic options. To uncover novel vulnerabilities, we employed complex-based analysis of the DepMap functional genomic data, identifying CDK8 as a dependency in aRMS. Both CDK8 knockout and pharmacologic inhibition impaired tumor cell growth and induced myogenic differentiation in vitro and in vivo. Compared to genetic loss, CDK8 pharmacologic inhibition induced more dynamic transcriptional changes. With a genome-scale CRISPR-Cas9 drug modifier screen, we determined that the maximal anti-tumor activity of the CDK8 inhibitor requires the presence of the Mediator kinase module, including CDK8, and transcriptional cooperation with the SAGA complex. We further identified SIX4 as a key transcription factor mediating CDK8 inhibitor-induced transcriptional activation of myogenic differentiation genes and impaired tumor proliferation. These findings suggest a distinct gain-of-function mechanism of the CDK8 inhibitor and establish a strong rationale for CDK8 inhibition as a differentiation-inducing therapeutic strategy in aRMS.
CDK12 mutations occur in 2-7% of metastatic prostate cancers (mPCa) and are considered to be exclusively somatic. Here, we identified five patients with mPCa (ages 44-62) harboring germline CDK12 truncating variants among 4,535 tested (0.1%). All had CDK12-driven cancers defined by an additional somatic CDK12 variant and the CDK12-specific hallmark genomic instability signature characterized by hundreds of tandem duplications. Two patients had multiple independent CDK12-driven tumors with distinct secondary somatic CDK12 variants. Germline CDK12 truncating variants were enriched in mPCa compared to gnomAD V4.1.0 controls (n=807,162; odds ratio 11.4, 95% CI 3.6-27.8) and V2.1.1 non-cancer controls (n=134,187; odds ratio 29.6; 95% CI 6.8-28.6). Family history revealed multiple related individuals with prostate or ovarian cancer, and germline variant inheritance was confirmed in the two tested pedigrees. Our data suggest that germline CDK12 truncating variants are a rare driver of lethal mPCa.
Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers and has a very poor prognosis. Ten to 15% are staged as resectable at diagnosis, and 5% to 15% downstaged with therapy to where surgery is feasible. Chemotherapy is a mainstay for all stages of PDAC. Targeted therapies are available for patients with select but expanding actionable genomic alterations. The tumor microenvironment provides a dense stroma with an immunosuppressive milieu that contributes to inherent treatment resistance of PDAC. Herein, we review current management of PDAC with a focus on emerging treatment paradigms, including targeted and immunomodulatory agents. SIGNIFICANCE:PDAC is a complex disease with unique genomic, immunologic, and clinical features. Recent developments in understanding of the pathobiology of this disease are translating into targeted and immunomodulatory therapies that will alter treatment paradigms and improve outcomes for this recalcitrant malignancy.
Biomolecular condensates formed via phase separation are emerging targets for pharmacologic or genetic manipulation for cancer therapy. In this commentary, we envisage that further deciphering the composition and the physicochemical properties of oncogenic condensates will provide unprecedented opportunities to develop novel strategies for cancer chemotherapy and immunotherapy.
Abstract Hepatocellular carcinoma (HCC) is a highly fatal tumor, for which risk stratification is crucial yet remains challenging. In this study, we develop an interpretable machine learning (ML) framework for HCC risk stratification based on routinely collected clinical data. We utilize prospectively collected multimodal data from more than 900,000 individuals and 983 cases of HCC across two population-scale cohorts: the UK Biobank study (development) and the All of Us Research Program (external testing). We assess individual and cumulative contributions of data modalities, including demographics, lifestyle, health records, blood, genomics, and metabolomics. Our final random forest–based models significantly outperform all publicly available state-of-the-art risk scores on both internal and external test sets. We demonstrate robustness across ethnic subgroups, provide comprehensive interpretability, and release all code, model weights, and a web calculator for external validation and agentic integration. Our study presents PRE-Screen-HCC, a robust and interpretable ML framework for HCC risk stratification and early detection. Significance: Using data from population-scale cohorts, we develop and externally validate an ML framework for HCC risk stratification. Models trained on routine clinical data outperform published scores, perform on par with metabolomics and genomics, generalize across subgroups, and remain interpretable. See related commentary by Foda, p. 1252
