Trends in Cancer

Epigenetic drivers of chromosomal instability 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.

Epigenetic drivers of chromosomal instability

The evolving landscape of brain metastasis: volume II

Orchestrating tumor-immune epigenetics via SERT–H3Q5ser axis

Mapping heterogeneity in the tumor microenvironment of renal cell carcinoma through single-cell omics 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.

Mapping heterogeneity in the tumor microenvironment of renal cell carcinoma through single-cell omics

Rethinking fairness in AI to improve current practice in oncology 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.

Rethinking fairness in AI to improve current practice in oncology

Cell Symposia: Hallmarks of cancer

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Chemotherapy-free cancer treatment – not for everyone yet 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.

Chemotherapy-free cancer treatment – not for everyone yet

Neural hijacking in cancer metabolism: from nutrients to organelles 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.

Neural hijacking in cancer metabolism: from nutrients to organelles

Interplay between cancer cell lipotypes and disease states 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.

Interplay between cancer cell lipotypes and disease states

Functional plasticity of RNA-binding proteins in cancer: both friend and foe 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.

Functional plasticity of RNA-binding proteins in cancer: both friend and foe

Tracing cancer progression through interpretable spatial multi-omics 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.

Tracing cancer progression through interpretable spatial multi-omics

Branched chain amino acids and their aberrant metabolism 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.

Branched chain amino acids and their aberrant metabolism in cancer

Tumor-intrinsic dichotomy shapes cellular heterogeneity in pancreatic cancer 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.

Tumor-intrinsic dichotomy shapes cellular heterogeneity in pancreatic cancer

The promise of TIL therapy for glioblastoma 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.

The promise of TIL therapy for glioblastoma

IL17-producing γδ T cells promote radioresistance via immunosuppression

Virus-mediated gene fusion: igniting and sustaining oncogenesis 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.

Virus-mediated gene fusion: igniting and sustaining oncogenesis

Mechanisms of whole-genome doubling in cancer evolution 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.

Mechanisms of whole-genome doubling in cancer evolution

A growing entourage for heterotypic circulating tumor cell clusters 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.

A growing entourage for heterotypic circulating tumor cell clusters

The very druggable RAS proteins 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.

The very druggable RAS proteins

Organellar pH as an emerging vulnerability to exploit in cancer 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 (pHi). 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 pHi 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.

Organellar pH as an emerging vulnerability to exploit in cancer

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RNA vaccines for cancer: revolutionizing immunization strategies 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.

RNA vaccines for cancer: revolutionizing immunization strategies

Advancing human leukocyte antigen-based cancer immunotherapy: from personalized to broad-spectrum strategies for genetically heterogeneous populations 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.

Advancing human leukocyte antigen-based cancer immunotherapy: from personalized to broad-spectrum strategies for genetically heterogeneous populations

Reprogramming T cell stemness against cancer Stem-like CD8+ T cells – characterized by high-level expression of the transcription factor TCF-1, and known as progenitor exhausted T (Tpex) cells – have emerged as crucial mediators of durable antitumor immunity. These cells demonstrate unique self-renewal capacity, multipotency, and enhanced responsiveness to immune checkpoint blockade therapy. This review synthesizes current understanding of Tpex cell biology, including their defining characteristics, tissue distribution, and functional importance in antitumor immunity. We focus particularly on innovative approaches to preserve and enhance T cell stemness through combination therapies, cytokine signal modulation, epigenetic regulation, tumor microenvironment modification, and microbiota-based interventions. The development of these next-generation immunotherapies targeting T cell stemness represents a transformative frontier in oncology, holding significant promise for improving therapeutic outcomes in cancer patients.

Reprogramming T cell stemness against cancer

Spatially resolving cancer: from cell states to therapy Recent advances in spatial multi-omics technologies and analytical methods are transforming our understanding of how cancer cells and their microenvironments interact to drive critical processes such as lineage plasticity, immune evasion, and therapeutic resistance. By linking cancer cell states, lineage plasticity, clonal dynamics, oncogenic pathways, and cellular interactions to their spatial context, these innovations provide deep biological insights and reveal clinically relevant molecular programs and spatial biomarkers. This review highlights key breakthroughs in spatial profiling and computational approaches, including integration with computational pathology, multimodal data, and machine learning to uncover important biological insights. We discuss challenges in spatial multimodal data integration and emerging clinical applications, and we propose a roadmap to accelerate clinical translation and advance precision oncology through spatially resolved, actionable, molecular insights.

Spatially resolving cancer: from cell states to therapy

How structural variation shapes the cancer epigenome It is widely recognized that cancer develops through a series of changes that modify the genomes of normal cells, enabling them to acquire new malignant properties. Epigenetic disruptions, which do not directly change the genetic sequence but rather influence how the genome is interpreted, have garnered significant attention as contributors to malignant transformation and progression. With the advent of new technologies to profile both the genome and epigenome of cancer cells simultaneously, the interplay between structural variation (SV) and epigenetic changes in malignancy is now an expanding field. In this review, we describe the key technological advances and highlight recent research exploring the relationship between SV and the epigenome in cancer.

How structural variation shapes the cancer epigenome

Canonical and non-canonical intricacies of MCL-1 in cancer Myeloid cell leukemia 1 (MCL-1), an antiapoptotic protein, belongs to the BCL-2 protein family and is an extensively studied anticancer target. MCL-1 inhibitors have been in development for decades but fall short on efficacy, toxicity, and side-effects. Recently, Brinkmann et al. shed light on the apoptosis-unrelated function of MCL-1 and its physiological role that could critically lead to MCL-1 inhibitor development.

Canonical and non-canonical intricacies of MCL-1 in cancer

Viral mimicry in cancer therapy Viral mimicry is a cellular state in which the reactivation of silenced transposable elements (TEs) leads to the accumulation of immunogenic nucleic acids, triggering innate immune pathways that resemble responses mounted against viral pathogens. Although they were first characterized in the context of epigenetic therapies, growing evidence indicates that other cancer treatment modalities – including radiotherapy, chemotherapies, and targeted therapies – can also induce TE reactivation and viral mimicry responses in cancer cells. This review synthesizes the current knowledge on treatment-induced TE-mediated immune responses in cancer, highlighting therapeutic strategies, shared and distinct molecular mechanisms, and their broader implications for tumor–immune interactions and treatment outcomes.

Viral mimicry in cancer therapy

CAR T cell persistence in cancer Chimeric antigen receptor T cell (CAR T) therapies are ‘living drugs’ in which T cells are genetically engineered to recognize and kill cancer cells. A major barrier to progress for CAR T targeting liquid and solid tumors is the poor persistence of these cells in vivo, which limits therapeutic efficacy. In this review, we summarize the field’s current understanding of CAR T persistence, including clinical observations, patient correlatives and multiomics approaches, and emerging cell engineering and manufacturing strategies. We also propose a conceptual framework for CAR T persistence to guide interpretation of clinical data and the design of more potent and efficacious CAR T therapeutics.

CAR T cell persistence in cancer

CX3CL1: a key switch of cell death immunogenicity CX3CL1 (fractalkine) is a unique chemokine with dual roles in cancer biology, capable of exerting both tumor-promoting and tumor-suppressive effects. Acting through its receptor CX3CR1, CX3CL1 facilitates immune evasion, angiogenesis, metastasis, and tumor cell survival and proliferation by recruiting immunosuppressive myeloid-derived suppressor cells. Conversely, it can enhance antitumor immunity by attracting cytotoxic T lymphocytes, natural killer cells, and dendritic cells into the tumor microenvironment. CX3CL1 has also been implicated in promoting immunogenic cell death–induced anticancer immune responses. However, excessive expression of CX3CL1 may paradoxically suppress immune activation, highlighting the importance of dose and context in its application. CX3CL1-based gene or mRNA therapies, particularly in combination with immune checkpoint inhibitors, show promising potential for cancer treatment.

CX3CL1: a key switch of cell death immunogenicity