Bacillus Calmette-Guerin (BCG) is the current standard of care for non-muscle invasive bladder cancer (NMIBC), but recurrence is common. Additional therapeutic options are a major unmet medical need for treating unresponsive patients. Stimulator of Interferon Genes (STING) plays a central role in mounting innate and adaptive immune responses to tumor cells, and activation of STING is a promising immunotherapeutic

Tumor-initiating cancer stem cells (CSC) pose a challenge in human malignancies since they are largely treatment resistant and can seed local recurrence and metastasis. Epigenetic mechanisms governing cell fate decisions in embryonic and adult stem cells are deregulated in CSCs. This review focuses on the methyltransferase DOT1L, which methylates H3K79 and is a key epigenetic regulator governing embryonic

RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Here, we developed a pan-RAS inhibitor, ADT-007, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis

Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the

Cdc2-like kinase 1 (CLK1) has dual-specificity kinase ability to phosphorylate tyrosine and serine/threonine protein residues. CLK1 regulates many physiological processes and has been shown to contribute to multiple types of cancer. Here, we investigated the functional role of CLK1 during intrahepatic cholangiocarcinoma (ICC) development. The expression of CLK1 was elevated in ICC tumors, and patients

As colorectal cancer (CRC) remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wildtype and mutant CRC with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and

C-reactive protein (CRP) has long been recognized as a marker of inflammation, but its evolving role in immunomodulation and cancer has increasingly been recognized. In recent years, multiple studies have explored CRP as a biomarker for prognosis and therapy response, particularly in the context of cancer immunotherapy. In this issue of Cancer Research, Feng and colleagues investigate the role of CRP

Cancer-associated fibroblasts (CAFs) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against pro-tumorigenic CAFs. Here, using single-cell RNA sequencing on patient

The batch effect is a nonbiological variation that arises from technical differences across different batches of data during the data generation process for acquisition-related reasons, such as collection of images at different sites or using different scanners. This phenomenon can affect the robustness and generalizability of computational pathology- or radiology-based cancer diagnostic models, especially

Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target

Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation

Targeting of the estrogen receptor (ER) by anti-estrogens is the standard-of-care for patients with ER+ HER2- advanced/metastatic breast cancer. While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure,

T cells within the tumor microenvironment frequently exhibit dysfunctional characteristics that compromise their ability to elicit both innate and therapeutic-induced immune responses. Regulators of immune dysfunction represent therapeutic targets to activate anti-tumor immunity. In this study, we identified semaphorin 3G (SEMA3G) as a key regulator of immune responses in cancer. SEMA3G was widely

Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. While adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of

Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a Forkhead box-family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2-C134W-dependent pharmacologic synergies, we created

Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of

ARID1A, a core constituent of SWI/SNF complex, is mutated in approximately 10% of colorectal cancers (CRC). While ARID1A deficiency corresponds to heightened immune activity in CRC, immune checkpoint inhibitors (ICIs) have shown limited efficacy in these tumors. The discovery of targetable vulnerabilities associated with ARID1A deficiency in CRC could expand treatment options for patients. In this

The tumor microenvironment plays a pivotal role in the metabolic reprogramming of cancer cells. A better understanding of the underlying mechanisms regulating cancer metabolism could help identify potential therapeutic targets. Here, we identified circEPB41(2) as a metabolically regulated circular RNA that mediates lipid metabolism in hepatocellular carcinoma (HCC). CircEPB41(2) was induced in response

Tumors utilize various mechanisms of HLA disruption in order to evade immune surveillance. Previous computational tools have interrogated specific aspects of this process, yet a holistic picture of HLA loss of heterozygosity (LOH), transcriptomic suppression, and alternative splicing has remained challenging. In a recent Nature Genetics study, Puttick and colleagues introduced MHC Hammer, a robust

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting

Spatial transcriptomics (ST) is a powerful tool for understanding tissue biology and disease mechanisms. However, the advanced data analysis and programming skills required can hinder researchers from realizing of the full potential of ST. To address this, we developed spatialGE, a web application that simplifies the analysis of ST data. The application spatialGE provided a user-friendly interface

Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing

Cancer-induced bone disease greatly diminishes the quality of life for patients with bone metastatic breast cancer, resulting in painful skeletal-related events including bone loss and fracture. Improved understanding of the roles of osteoblasts and osteoclasts, and how tumors alter their biology, has led to blockbuster therapies that significantly reduce skeletal-related events, but the disease remains

Breast cancer subtypes display different metastatic organotropism. Identification of the mechanisms underlying subtype-specific organotropism could help uncover potential approaches to prevent and treat metastasis. Herein, we found that FOXF2 promoted the seeding and proliferative recovery from dormancy of luminal breast cancer (LumBC) and basal-like breast cancer (BLBC) cells in the bone by activating

Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals

Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in FH-deficient tumors. The screen identified chromodomain helicase DNA binding protein 6 (CHD6) as an essential regulator of the growth of FH-mutated

DHX9 is a multifunctional DExH-box RNA helicase with important roles in the regulation of transcription, translation, and maintenance of genome stability. Elevated expression of DHX9 is evident in multiple cancer types, including colorectal cancer (CRC). Microsatellite instable-high (MSI-H) tumors with deficient mismatch repair (dMMR) display a strong dependence on DHX9, making this helicase an attractive

T cell exhaustion remains a significant barrier to immunotherapeutic success for many patients with solid tumors. Growing evidence suggests that enhanced survival and self-renewal properties of a stem-like precursor T cell population (Tpex) is correlated with a survival advantage in immunotherapy. In a recent study published in Science, Kang and colleagues find three epigenetic regulators commonly

During metastasis, cancer cells detach from the primary tumor, circulate through the bloodstream, and establish themselves at distant sites, facing increased levels of reactive oxygen species (ROS) that act as significant barriers to metastatic progression. Adapting to and surviving in these high-ROS environments is thus crucial for successful metastasis. A recent study by Nease and colleagues identified

Lung cancer is the most common cause of cancer mortality globally, and the prevalence of lung adenocarcinoma (LUAD), the most common lung cancer subtype, has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. Here, we performed whole exome-sequencing

Approximately 35% of long-term cancer survivors experience ongoing cancer-related cognitive impairment (CRCI). Yet, few efficacious interventions exist to prevent or ameliorate CRCI. The underlying biological processes driving CRCI are complex and are reported to include changes in brain structure and function, increased oxidative stress and inflammation, and alterations in gut microbiome composition

Biliary tract cancer (BTC), encompassing diseases such as intrahepatic (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), is not only on the rise but also poses a significant and urgent health threat due to its high malignancy. Genomic differences point to the possibility that these subtypes represent distinct diseases. Elucidation of the specific distribution of T cell subsets

Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights

Aging in mammals, including humans, is marked by a multitude of molecular, cellular, and systemic changes that increase the risk of various diseases, including cancer. While the link between aging and increased cancer incidence is well documented, the precise biological mechanisms driving tumor initiation remain less clear. In a recent issue of Cancer Cell, Yan and colleagues have identified Midkine

Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor

A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and

Epithelial-to-mesenchymal transition (EMT) is known to play roles in orchestrating cellular plasticity across many physiological and pathological contexts. Partial EMT, wherein cells maintain both epithelial and mesenchymal features, is gaining recognition for its functional importance in cancer in recent years. There are many factors regulating both partial and full EMT, and the precise mechanisms

Tumor-associated microglia and macrophages (TAM) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment. Given the heterogeneity and plasticity of TAMs in the GBM tumor microenvironment, understanding the context-dependent cancer cell–TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell

Genetic alterations play a pivotal role in various human diseases, particularly cancer. The androgen receptor (AR) is a crucial transcription factor driving prostate cancer (PCa) progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7.

c-MYC is an important driver of high-risk neuroblastoma. A lack of c-MYC–driven genetically engineered mouse models (GEMM) has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and to develop effective therapies. Here, we showed that conditional c-MYC induction via Cre recombinase driven by a tyrosine hydroxylase (Th) promoter led to a preponderance of PDX1+ somatostatinoma

Immunogenic cell death (ICD) induces an active immune response. Activating ICD represents a potential approach to boost the anti-tumor activity of immunotherapy, highlighting the need to identify effective and safe ICD inducers. In this study, we identified a conserved, ICD-related circular RNA cEMSY by systematically screening ICD models induced by multiple cell stressors in lung adenocarcinoma (LUAD)

Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A

Inducing ferroptosis in tumor cells is emerging as a strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis of immune cells in the tumor microenvironment (TME) need to be better understood in order to realize the potential of this approach. In this study, we discovered that neutrophils in chemoresistant breast cancer are

Melanoma brain metastasis is associated with high morbidity and mortality and remains a major clinical challenge. Despite recent successes with combination immune checkpoint inhibitors (ICI) in the treatment of affected patients, the mechanistic underpinnings of T cell entry and response to these drugs in brain metastasis are poorly understood. Using real-time intravital microscopy, Messmer and colleagues

Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides

The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched

Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may

Cleavage stimulation factor subunit 2 (CSTF2) is a fundamental factor in the regulation of 3'-end cleavage and alternative polyadenylation of pre-mRNAs. Previous work has identified a tumor-promoting role of CSTF2, suggesting that it may represent a potential therapeutic target. Here, we aimed to elucidate the mechanistic function of CSTF2 in hepatocellular carcinoma (HCC). CSTF2 upregulation was frequent

The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial

Overexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. Here, we found that PHGDH is universally increased in melanoma cells and required for melanomagenesis. While PHGDH amplification explained PHGDH overexpression in a subset of melanomas, oncogenic

Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving

Internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase-3 (FLT3) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with poor prognosis. FLT3-ITD mutations result in endoplasmic reticulum (ER) retention and constitutive autophosphorylation of FLT3. The PR/SET domain 16 (PRDM16) is highly expressed in FLT3-ITD+ AML patients, suggesting it might

Central nervous system neuroblastoma with FOXR2 activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the

Therapeutic resistance to androgen receptor (AR)–targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence

Pancreatic ductal adenocarcinoma is a deadly disease and is projected to become the second leading cause of cancer-related death by 2030. A major hallmark is the exuberant host response comprising the tumor microenvironment, of which, cancer-associated fibroblasts (CAF) are a prevalent component. Despite the gains in understanding of their heterogeneity and functionality from CAF studies in recent

Anti-cancer therapies can induce cellular senescence, which is highly stable, or drug-tolerant persistence, which is efficiently reversed upon therapy termination. While approaches to target senescent cells have been extensively studied, further understanding of the processes regulating persistence is needed to develop treatment strategies to suppress persister cell survival. Here, we used mTOR/PI3K

Cancers frequently co-opt lineage-specific transcription factors (TFs) utilized in normal development to sustain proliferation. However, the effects of these TFs on tumor development depend considerably on where in the genome they bind. A new paper by Taylor and colleagues expands on previously developed diamidine compounds that obstruct the DNA binding sites of the pioneer TF PU.1 (SPI1) in acute

Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables