Platelets: the next-generation ovarian cancer biomarker? The diagnosis and monitoring of ovarian cancer remain major clinical challenges due to nonspecific symptoms, late-stage detection, and high rates of recurrence. Increasing evidence suggests that circulating platelets reflect tumor presence and activity. Platelet-based molecular and functional signatures may, therefore, represent a promising new class of biomarkers for ovarian cancer.

Platelets: the next-generation ovarian cancer biomarker?

Neural circuits in lung adenocarcinoma modulate immunosurveillance Recent evidence from a study published in Nature by Wei et al. reveals a bidirectional tumor–brain axis in lung cancer that suppresses immune surveillance by reprogramming macrophages and disabling T cell responses. These findings highlight neuroimmune signaling as a key regulator of cancer progression and a promising therapeutic target.

Neural circuits in lung adenocarcinoma modulate immunosurveillance

Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion T cell exhaustion is an adaptive dysfunctional state driven by chronic antigen exposure and an immunosuppressive tumor microenvironment, which significantly impedes effective antitumor immunity and T cell therapies. This progressive loss of effector function and memory potential is governed by the complex and coordinated interplay of epigenetic, transcriptional, epitranscriptomic, and metabolic networks, which collectively establish stable exhaustion-associated programs. Emerging evidence demonstrates that modulating these layers, whether permanently or transiently, can reverse exhaustion and reinvigorate T cell function. Furthermore, core metabolites serve as shared cofactors, directly linking cellular metabolism to these epigenetic and epitranscriptomic changes. Characterizing these multilayered regulatory mechanisms is critical for developing novel strategies to reprogram exhausted T cells and improve therapeutic efficacy against cancer.

Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion

LGR5: from stem cell marker to therapeutic target Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is an established marker of normal and cancer stemlike cells. LGR5 has been implicated in promoting cancer cell plasticity that drives tumorigenesis, metastasis, and therapeutic resistance. LGR5 rapidly and constitutively internalizes and potentiates Wnt (Wingless/Int-1)/β-catenin and adhesion signaling pathways, though its precise mechanisms and interacting partners remain unresolved. An improved understanding of LGR5 signaling may provide invaluable insight into its intricate and important functions in cancer progression. Moreover, several LGR5-targeting therapies, including peptibody– and antibody–drug conjugates and bispecific antibodies, are showing promising efficacy and tolerability in colorectal cancer and other tumor types. This review discusses the cancer-related functions of LGR5 and explores the preclinical and clinical approaches to therapeutically target this enigmatic protein.

LGR5: from stem cell marker to therapeutic target

Toward mutational epidemiology: using mutational signatures of environmental exposures to assess cancer risk Exposure to environmental mutagens increases cancer risk, yet exposure-detection methods often lack standardization and sensitivity. Genotoxic agents leave characteristic ‘mutational signatures’ in DNA, creating permanent, quantitative records of past exposures. Analyses of these signatures have clarified the mutational impacts of many established carcinogens and implicated contributions of previously unrecognized ones. Recent studies indicate that signatures of environmental exposures may be detectable in readily accessible human tissues, providing a basis for population-scale monitoring—termed ‘mutational epidemiology’—which could complement conventional approaches to refine and accelerate the identification of mutagenic carcinogens. Realizing this potential will require identifying accessible tissues that capture mutations from specific exposure types and routes, defining signature profiles within those tissues, and determining how well they reflect mutagenesis in cancer-prone organs.

Toward mutational epidemiology: using mutational signatures of environmental exposures to assess cancer risk

From prediction to precision: how immunopeptidomics advances neoantigen discovery T cell recognition of peptides presented by class I and II human leukocyte antigen (HLA) molecules is fundamental to cancer immunity and personalized immunotherapy. Neoantigens, peptides containing somatic mutations, are attractive therapeutic targets due to their tumor specificity and immunogenicity. Current neoantigen discovery pipelines rely on sequencing and computational predictions but often struggle to identify peptides that are both presented and immunogenic. Immunopeptidomics, which uses mass spectrometry to identify naturally presented HLA-bound peptides, enables detection of neoantigens displayed on tumor cells. This review explores how immunopeptidomics complements existing tools to refine neoantigen identification, improves machine learning prediction algorithms through immunopeptidomics-derived datasets, and distinguishes between mutant and wild-type immunopeptides. We also highlight emerging developments that will further integrate immunopeptidomics into personalized immunotherapy.

From prediction to precision: how immunopeptidomics advances neoantigen discovery

Unexpected role of the integrated stress response in cancer immune evasion Viral mimicry, i.e., the ability of uninfected cancer cells to emit molecular signals normally associated with infection, is paramount for anticancer immunity. Recent findings from Bossowski et al. indicate that the integrated stress response (a crucial component of cellular responses against infection) can unexpectedly promote immune evasion via an LCN2-driven, macrophage-dependent mechanism.

Unexpected role of the integrated stress response in cancer immune evasion

Mesothelioma: a systemic therapy clinical trials snapshot

Dissecting histological transformation The adaptive nature of cancer is a major obstacle limiting durable treatment responses. Histological transformation (HT) is a process whereby one cancer changes into a categorically different tumor type, often following treatment with targeted therapy. Best characterized in lung and prostate adenocarcinomas, HT is particularly disconcerting because the resultant cancer no longer depends on the initial oncogenic driver program, is therapeutically recalcitrant, and is often highly metastatic. Partly because HT is technically difficult to study, this process remains poorly described. As newer therapies broaden the scope of oncogenic drivers that can be targeted, HT may become more prevalent, highlighting the need for further research to dissect these phenomena. We propose that modern experimental and analytical tools present an opportunity to advance our understanding and improve our clinical management of histologically transforming cancers.

Dissecting histological transformation

In vivo CAR T cell engineering: design principles and open questions Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, leading to seven FDA-approved products, but widespread adoption has been limited by costly and complex manufacturing and administration. Several methods have emerged to directly reprogram T cells within patients, with the potential to simultaneously improve potency, reduce costs, and broaden accessibility. While early clinical studies demonstrate safety and therapeutic activity, critical questions remain regarding long-term efficacy, the interplay between means of delivery and host biology, and optimal disease indications for each delivery approach. This review summarizes the preclinical and clinical data for state-of-the-art viral and nonviral approaches for in vivo CAR-T engineering, discusses their opportunities and limitations, and highlights key open questions that will shape the maturation of this emerging field.

In vivo CAR T cell engineering: design principles and open questions

p53: defender of lineage fidelity and foe of plasticity in cancer and regeneration Although p53 plays a vital role in tumor suppression, the molecular programs underlying its tumor suppressor function remain incompletely understood. Recent work coupling genetically engineered mouse models and single-cell RNA sequencing has illuminated new aspects of p53 function in governing cell state changes. During both lung adenocarcinoma suppression and lung injury repair, p53 acts in a plastic transitional cell state to drive alveolar type 1 cell differentiation, while p53 deficiency causes transitional cell persistence and cancer progression or tissue damage. New insights into p53 function in injury repair in other tissues have also emerged, including in injury-induced intestinal revival stem cells. These studies underscore the importance of p53 in specific plastic states, where it coordinately enforces differentiation and restrains lineage infidelity during tissue healing and cancer suppression.

p53: defender of lineage fidelity and foe of plasticity in cancer and regeneration

Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis Understanding tumor initiation is crucial for early interception and prevention. Tumors arise from genetic alterations and microenvironmental changes that together create a niche for malignant growth. Previously, the spatiotemporal dynamics of tumorigenesis were difficult to study. Recent advances in high-resolution intravital microscopy, tissue clearing, and spatial molecular profiling enable direct visualization of mutated cells and clones within their microenvironment in situ. These tools transform tumor initiation from a theoretical construct into a mechanistically dissectible process. Here, we synthesize recent insights into how mutated clones expand or regress, how clonal dynamics drive transformation, and how niche signals shape tumor-initiating cell fate. We highlight key imaging innovations and outline limitations and opportunities for capturing tumor initiation in vivo.

Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis

Driving CAR therapies beyond T cells Chimeric antigen receptor (CAR)-T cell therapy has reshaped cancer immunotherapy for hematological malignancies, yet progress in solid tumors remains limited. Physical barriers, antigen heterogeneity, and immunosuppressive tumor microenvironment restrict the activity and persistence of CAR-T cells, while safety concerns complicate target selection. Extending CAR technology to alternative immune lineages, such as macrophages, natural killer cells, tumor-infiltrating lymphocytes, and unconventional T cells, offers complementary mechanisms for tumor recognition, infiltration, and immune modulation. This review highlights recent advances in these emerging CAR platforms, compares their biological and translational features, and outlines how integrating cell-intrinsic properties with CAR design may guide the next generation of cellular immunotherapies for solid tumors.

Driving CAR therapies beyond T cells

Epigenetic dysregulation and microenvironment remodeling in pancreatic cancer Epigenetic dysregulation including frequent mutations in epigenetic regulators alongside nonmutational reprogramming driven by oncogenic and metabolic stresses represents a hallmark of pancreatic ductal adenocarcinoma (PDAC). Recent advances using low-input epigenomics and single-cell technologies have revealed their role in fostering cellular plasticity, stromal reprogramming, immune evasion, and therapy resistance. This review synthesizes current knowledge of epigenetic mechanisms in PDAC pathogenesis, highlighting their stage- and context-dependent roles in tumor progression, tumor microenvironment crosstalk, and metabolic adaptation. We further highlight emerging therapeutic strategies that target epigenetic vulnerabilities. By integrating cutting-edge epigenomic profiling with functional studies, we outline a road map for translating epigenetic discoveries into clinical strategies against this lethal malignancy.

Epigenetic dysregulation and microenvironment remodeling in pancreatic cancer

Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems The Hallmarks of Cancer framework provided a unifying description of tumor capabilities, but in its static form, it cannot capture where in a tumor these traits occur, when they arise, or how they reorganize under selection pressure. Here, we propose Spatiotemporal Hallmark Ecosystems as a new lens that redefines the functional unit of selection in cancer evolution. In this view, hallmarks are not fixed consequences of mutations but context-dependent phenotypes that are enabled or constrained by local tissue and microenvironmental conditions. This perspective resolves critical paradoxes, explaining why identical mutations yield divergent outcomes, why premalignant states persist without transformation, and how therapeutic resistance emerges not just from clonal selection but also from ‘ecological buffering’ by the tumor architecture. By shifting the analysis from the individual cell to the ecosystem, we outline a path toward predictive biomarkers and spatially aware strategies that target the structural stability of the tumor.

Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems

A lysosomal requiem for glioblastoma cells Once viewed solely as degradative compartments, lysosomes shape cell fate through signaling, metabolism, and communication. In glioblastoma, their rewiring underlies plasticity, invasion, and resistance to therapies. This forum explores lysosomal dynamics in brain tumors and therapeutic strategies targeting lysosomal vulnerabilities, offering fresh perspectives for precision approaches in this lethal cancer.

A lysosomal requiem for glioblastoma cells

The redox paradox in HGGs: ROS as drivers and destroyers Reactive oxygen species (ROS) are essential second-messenger molecules, yet when deregulated, they fuel cancer growth and therapeutic resistance. In high-grade gliomas, including glioblastoma, diffuse hemispheric glioma, and diffuse midline glioma (DMG), genetic, epigenetic, and metabolic alterations drive chronic ROS production and redox imbalance. This oxidative stress promotes DNA damage, epigenetic reprogramming, tumor growth, and immune escape. In DMG, global DNA and histone hypomethylation are amplified by oxidative stress, while ROS-dependent Ras/Raf/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathways reinforce tumor survival. Paradoxically, the same ROS create an intrinsic vulnerability as excess ROS can overwhelm defenses and trigger cytotoxicity. Targeting ROS is challenging; however, new strategies, including NADPH oxidase inhibition, metabolic modulation, and ROS-inducing therapies, reveal vulnerabilities. Understanding this redox paradox is critical to exposing therapeutic vulnerabilities and improving outcomes for patients with these deadly cancers.

The redox paradox in HGGs: ROS as drivers and destroyers

Advancements in organoid models emulating metastatic niches Metastases cause most cancer-related deaths, underscoring the need for therapies targeting metastatic stages, including the tumor microenvironment. Yet translating biological insights into treatments remains difficult. Preclinical metastasis research largely relies on rodent models, which have species-specific limitations and are incompatible with large-scale perturbation screens in a human context. Human organoids aim to emulate organ microenvironments in vitro and, when cocultured with cancer cells, can provide complementary models. These ‘chimeroids’ may enable scalable studies of cancer–microenvironment interactions and support genetic and pharmacological screens to discover new targets, offering insights into the final, often lethal step of metastasis—tissue colonization. This review summarizes advances in stem cell-derived organoid models for organs frequently affected by solid tumor metastases, including the brain, lung, liver, and bone, and evaluates their ability to recreate physiologically relevant niches for studying cancer cell adaptation and colonization.

Advancements in organoid models emulating metastatic niches

IL33 in pancreatic cancer—pro- or antitumor? Interleukin 33 (IL33) in the tumor microenvironment of pancreatic cancer has been linked to both pro- and antitumor immune responses, suggesting a context-dependent role. Herein, we discuss the current understanding and challenges of therapeutically targeting IL33 signaling in pancreatic cancer.

IL33 in pancreatic cancer—pro- or antitumor?

The rationale for targeting nectin-4 in pancreatic cancer Nectin-4 is an immunoglobulinlike cell adhesion molecule that contributes to tumor aggressiveness and immune evasion in pancreatic ductal adenocarcinoma (PDAC). Its high and selective expression on pancreatic cancer cells, together with the clinical efficacy of nectin-4-targeted antibody–drug conjugates in other solid tumors, establishes nectin-4 as a compelling therapeutic target in PDAC.

The rationale for targeting nectin-4 in pancreatic cancer

Ammonia: a metabolic checkpoint for Treg potency Ammonia acts as a metabolic checkpoint fueling regulatory T cells (Tregs). Gu et al. demonstrate that utilizing argininosuccinate lyase-linked survival buffering and a FOXP3-spermine-PPARγ axis for mitochondrial reinforcement allows Tregs to convert toxic waste into suppressive power, driving tumor immune evasion and immunotherapy resistance.

Ammonia: a metabolic checkpoint for Treg potency

Disarming cancer resistance: FAK as a therapeutic target

FGFR rearrangements: oncogenic drivers and therapeutic targets

Nociceptive neuroimmune circuit drives immune evasion Tumor-associated sensory nerves are emerging regulators of cancer immunity, yet their role in systemic immunosuppression remains unclear. Zhang et al. revealed that tumors hijack an interorgan nociceptor–slit guidance ligand 2–calcitonin gene-related peptide circuit to escape immune surveillance. Disrupting this neural loop restores T-cell function and enhances immunotherapy efficacy.

Nociceptive neuroimmune circuit drives immune evasion

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MAX in cancer: dynamic role of MYC’s partner-in-crime MAX is the essential binding partner of MYC, necessary for MYC-dependent transcriptional activation. Depending on the context, MAX can function as a tumor suppressor or promote tumorigenesis in an MYC-driven manner. Here, we highlight the key discoveries defining the role of MAX in cancer and the current research gaps.

MAX in cancer: dynamic role of MYC’s partner-in-crime

Melanoma-secreted melanosome-MHC I disrupts T cell antitumor immunity

ALPK1 agonists ignite innate immunity in anticancer therapy A recent study published in Nature by Tian et al. identifies UDSP-Hep as a synthetic agonist of the innate immune receptor Alpha-protein kinase 1 (ALPK1) that induces enhanced antitumor activity compared with the canonical ALPK1 agonist ADP-Hep and Toll-like receptor or stimulator of interferon genes agonists. UDSP-Hep drives the tumor microenvironment toward a proinflammatory, antitumor state.

ALPK1 agonists ignite innate immunity in anticancer therapy

Evolving approaches to broaden public and patient involvement in cancer research Public and Patient Involvement (PPI) integrates patients and the public into research design, conduct, and dissemination to ensure future research represents the needs of society. We propose a toolkit for researchers, based on outcomes from an ovarian cancer PPI project, to incorporate meaningful, representative cancer research into future studies.

Evolving approaches to broaden public and patient involvement in cancer research

Mechanistic cancer prevention comes of age Historically underfunded and dominated by epidemiological and behavioural research, cancer prevention is now able to embrace mechanistic insights that enable targeted, biologically grounded interventions. As a new generation of mechanistically based strategies begins to take shape, cancer prevention is poised to enter a new era.

Mechanistic cancer prevention comes of age