The serotonin transporter (SERT) and histone H3 serotonylation (H3Q5ser) integrate extracellular neurotransmitter signals to chromatin regulation in cancer. Here, we discuss how the SERT-H3Q5ser axis shapes tumor immunity and epigenetic plasticity, and highlight emerging strategies to therapeutically target this neuro-epigenetic interface.

Chromosomal instability (CIN) fuels phenotypic cancer heterogeneity through heritable epigenetic defects, hence driving disease initiation, progression, and resistance to therapy. Two recent studies, by Bai et al. and Salinas-Luypaert et al., demonstrate that imbalanced histone or DNA methylation actively promotes CIN by disrupting centrosome homeostasis or centromere integrity, globally linking epigenetic dysregulation to mitotic failure and genome instability.

Brain metastasis (BrM) represents the most common intracranial malignancy, arising in up to 30% of all adult cancer patients and contributing significantly to cancer-related morbidity and mortality. BrM is now recognized as a biologically distinct condition with unique mechanisms of organotropism, colonization, and therapeutic vulnerability. We highlight recent progress in omic and spatial profiling, which has revealed key drivers of brain tropism. These findings have reshaped therapeutic strategies, leading to clinical trials that specifically address central nervous system (CNS) involvement. Emerging approaches now include efforts to prevent brain relapse. Preclinical models increasingly provide sophisticated platforms to evaluate next-generation therapies. Collectively, these advances are transforming the clinical landscape, offering new hope for the prevention and management of BrM through precision medicine and integrated therapeutic strategies.

Renal cell carcinoma (RCC) outcomes are shaped by a complex tumor microenvironment (TME), where malignant cells represent only a minority of the tissue. Recent advances in single-cell technologies - including single-cell RNA sequencing, single-nucleus RNA sequencing, single-cell assay for transposase-accessible chromatin sequencing, single-cell T-cell receptor sequencing, and imaging mass cytometry - have uncovered the cellular, regulatory, and spatial heterogeneity of RCC. Here, we synthesize insights from these approaches to define diverse CD8 T-cell subsets and exhaustion trajectories, as well as the origins, phenotypic diversity, and functional states of other immune cells including tumor-associated macrophages, dendritic cells, natural killer cells and cancer-associated fibroblasts. Together, these findings highlight the transformative potential of single-cell technologies to unravel TME complexity, identify biomarkers of therapeutic response, and guide precision immunotherapy in RCC.

Cytotoxic chemotherapy (CC) has long been the cornerstone of treatment in oncology, but primary resistance, the emergence of secondary resistance, and toxicity remain significant challenges. We explore how precision oncology aims to replace conventional chemotherapy through its enhanced antitumoral activity and reduced toxicity. We highlight significant progress in this area and emphasize recent clinical trials where targeted therapies and immunotherapy have yielded superior outcomes. Despite significant advances in cancer understanding and molecular profiling, in the coming years CC will likely remain a standard treatment for diseases that are not accessible to precision oncology or immunotherapy, as a rescue treatment for many cancers, or in combinations with new agents.

Fairness in artificial intelligence (AI) is often assessed with flawed metrics, particularly in oncology where patient diversity and structural inequities shape outcomes. Ground truth labels, predictions, and demographic attributes all carry biases that distort fairness evaluations. We argue for rethinking fairness frameworks to better capture equity in cancer care.

Human papillomavirus (HPV) integration is known to cause host genome instability and subsequent structural variants. Recently, Khan and colleagues thoroughly characterized a recurrent FGFR3-TACC3 fusion caused by HPV integration in oropharyngeal squamous cell carcinoma (OPSCC) identifying synergistic interplay with HPV E6/E7 required for transformation. These findings reveal another mechanism in which virus integration can ignite tumorigenesis and a promising avenue for future investigation.

IL17-secreting γδ T cells promote immunosuppression, metastatic dissemination, and resistance to treatment in various oncological settings. Recent findings from Deng et al suggest that DNA-containing extracellular vesicles released from irradiated lung cancer cells favor radioresistance by orchestrating the recruitment of IL17-secreting γδ T cells via a CCL20-dependent mechanism involving STING signaling in tumor-associated macrophages.

Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated efficacy in refractory melanoma and durable responses in lung cancer. Glioblastoma presents distinct challenges for immunotherapy, including profound tumor heterogeneity, low T cell infiltration, and an immunosuppressive microenvironment, but these same features highlight the unique rationale for TILs. Unlike monoclonal engineered approaches, TILs retain natural polyclonality, enabling recognition of a diverse set of tumor-associated antigens and potential adaptation to the evolving antigenic landscape. Preliminary studies have already shown that tumor-reactive TILs can be successfully isolated and expanded from glioblastoma specimens, providing feasibility for clinical translation. This review discusses the current landscape of TIL therapy in glioblastoma, highlights recent advancements, and discusses future directions and clinical translation to position TIL therapy as a promising and adaptable cellular immunotherapy for one of the most treatment-resistant human cancers.

Intratumoral heterogeneity in pancreatic cancer poses a significant challenge, contributing to disease aggressiveness and complicating treatment. A recent study by Li et al. reveals that this heterogeneity is maintained by tumor-intrinsic reciprocal signaling between SPP1 and GREM1 in the epithelial and mesenchymal cell populations of pancreatic cancer.

Multi-omics integration is reshaping cancer research by combining histopathology, transcriptomics, and proteomics with spatial and temporal context. Schweizer et al. revealed compartment-specific biology, RNA-protein decoupling, and emergent molecular patterns underpinning malignant transformation in low-grade serous carcinoma, highlighting the potential of integrated multi-omics to uncover novel mechanisms and guide precision oncology.

RNA-binding proteins (RBPs) govern RNA-based post-transcriptional processes that generate the abundance and diversity of the proteome. RBPs have recently emerged as crucial cancer regulators that can influence multiple cancer hallmarks. However, many RBPs display remarkable variations across different tumor types and can exert both tumor-promoting and tumor-suppressive effects. These opposing roles are often attributed to context-dependency, but there is a distinct lack of clarity regarding what aspects of cellular context define the differences in the roles of RBPs. Given the recent development of RBP-targeted interventions, resolving this significant gap in the field could improve the selectivity and specificity of RBP biomarkers and therapies in cancer. This review analyzes recent findings and explores the mechanisms by which the functional plasticity of RBPs in tumorigenesis may arise.

While the initial transformation of cancer cells is driven by genetic alterations, tumor cell behaviors and functional states are dynamically regulated by cell-intrinsic factors including proteins, metabolites and lipids, and extrinsic microenvironmental factors. Emerging multi-omics technologies highlighted that cancer cells exhibit distinct lipidome compositions and employ specific lipid metabolic circuits for chemical conversions - collectively defined as 'lipotypes'. We review the interplay between cancer lipotypes and cellular states, focusing on interpreting how being at different positions along the spectra of representative lipid metabolic axes influences cancerous traits. We aim to instill a system biology perspective to integrate 'lipotypes' into the established 'genotype-phenotype' framework in cancer.

Tumors dynamically interact with the central and peripheral nervous systems, hijacking neural plasticity and reprogramming metabolism in a bidirectional manner to drive cancer progression. Neural inputs reshape the metabolism of cancer cells and their microenvironment - glycolysis, oxidative phosphorylation, and lipid metabolism - while tumors exploit neuronal nutrients and mitochondria to thrive under metabolic stress. This review explores neurocancer metabolic crosstalk through multiple mechanisms by three principal modes of interaction, highlighting how targeting these metabolic interdependencies could disrupt tumor progression. By integrating cancer metabolism and neuroscience, it offers a conceptual framework for understanding neural-tumor metabolic circuits in malignancy and identifies potential therapeutic vulnerabilities.

Whole-genome doubling (WGD) has recently emerged as one of the most common genomic alterations in cancer and is associated with genomic instability, drug resistance, and metastasis. However, WGD also generates unique vulnerabilities that create a therapeutic window between cancer cells and healthy cells. Over the past few years, there has been a rapid growth in our understanding of WGD at a molecular level. In this review, we discuss the causes and immediate cellular effects of, and therapeutic considerations for, WGD in cancer.

Cancer cells require sufficient nutrients to support biomass generation, rapid proliferation, and survival. Thus, extensive reprogramming of amino acid metabolism is necessary for tumor initiation and progression under strenuous conditions. One metabolic pathway that has garnered attention is branched chain amino acid (BCAA) catabolism, a pathway that is highly altered across malignancies. This review examines current insights into how circulating BCAAs and their aberrant catabolic enzymes impact both cancer cells and the surrounding tumor microenvironment.

Human leukocyte antigen (HLA)-based immunotherapeutics, such as tebentafusp-tebn and afamitresgene autoleucel, have expanded the treatment options for HLA-A*02-positive patients with rare solid tumors such as uveal melanoma, synovial sarcoma, and myxoid liposarcoma. Unfortunately, many patients of European, Latino/Hispanic, African, Asian, and Native American ancestry who carry non-HLA-A*02 alleles remain largely ineligible for most current HLA-based immunotherapies. This comprehensive review introduces HLA allotype-driven cancer health disparities (HACHD) as an emerging research focus, and examines how past and current HLA-targeted immunotherapeutic strategies may have inadvertently contributed to cancer health disparities. We discuss several preclinical and clinical strategies, including the incorporation of artificial intelligence (AI), to address HACHD. Last, we emphasize the urgent need for further research to better understand HLA allotype heterogeneity and its influence on tumor immunopeptidome-driven immune responses. We anticipate that these strategies will accelerate the development and implementation of both personalized and broad-spectrum HLA-based immunotherapies, and will ultimately improve cancer treatment across genetically heterogeneous patient populations worldwide.

Cancer vaccines have emerged as a promising strategy in cancer immunotherapy, capable of eliciting robust antitumor immune responses by targeting tumor-associated antigens or tumor-specific antigens. Among the various vaccine platforms, RNA-based vaccines have garnered substantial attention, especially in light of the success of mRNA vaccines during the COVID-19 pandemic. This review outlines the fundamental characteristics of different RNA vaccine modalities, summarizes recent clinical applications in cancer treatment, and highlights strategies aimed at improving their efficacy and safety. Furthermore, we discuss the current challenges facing RNA vaccine development and offer perspectives on future directions in this rapidly advancing field.

Circulating tumor cell (CTC) clusters have emerged as key mediators of cancer spread. Among these, heterotypic CTC clusters exemplify how cooperative interactions between different cell types may enhance metastasis efficiency. Recent studies by Scholten et al. and Schuster et al. uncover additional immune cell partners, including T cells and monocytes, involved in shaping CTC biology.

Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pH). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pH provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

RAS genes encode molecular switches that control cell growth and survival, and their oncogenic mutations drive many cancers. Once deemed 'undruggable', RAS is now being challenged by innovative inhibitors. Recent advances, reported by Stanland and Huggins et al. and Feng et al., include EFTX-G12V, an EGFR-directed allele-specific RNAi therapeutic, and MCB-36, a dual-state pan-KRAS degrader, exemplifying precision RAS-targeted strategies.