Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment and exhibit remarkable functional plasticity, acting as either immunosuppressive cells that promote tumor progression or immunostimulatory cells that can support antitumor immunity, depending on the prevailing microenvironmental cues. These cells promote angiogenesis, metastasis, immune suppression, and therapy resistance. However, when appropriately reprogrammed, TAMs can directly kill or phagocytose cancer cells and/or activate antitumor T cell and natural killer cell responses. In this article, we review current therapeutic strategies targeting TAMs, including approaches directed against macrophage-associated receptors, signaling pathways, and epigenetic and metabolic regulators. We also discuss emerging TAM-targeted therapeutic modalities, including cytokine-based therapies, cell-based therapies, bispecific antibodies, macrophage-targeted nanoplatforms, and anti-TAM chimeric antigen receptor T-cell approaches, highlighting their potential to enhance antitumor immunity and improve clinical outcomes.

Repeated Phase 3 failures have framed proficient mismatch repair/microsatellite stable colorectal cancer as ‘cold’ and immunotherapy-resistant. We argue that this resistance is conditional, shaped by disease stage, metastatic anatomy, spatial immune architecture, and therapeutic mechanism. Recognizing these principles can guide patient selection, biomarker stratification, and drug development to realize immunotherapy’s clinical potential.

Tumor-agnostic drug development reframes oncology around shared molecular dependencies rather than tissue origin, enabling efficient development for rare, actionable drivers across tumors. Since the first tumor-agnostic approval in 2017 for immunotherapy in microsatellite instability-high or mismatch repair-deficient tumors, the regulatory paradigm has expanded to high tumor mutation burden (TMB-H) cancers, oncogene-directed kinase inhibitors, such as NTRK, rearranged during transfection (RET), BRAF valine-to-glutamic acid substitution at codon 600 (BRAF V600E), and antibody–drug conjugate targeting Her2 overexpression, establishing proof of principle across modalities. In this review, we examine current tumor-agnostic approvals and emerging targets with pan-cancer potential: Kirsten rat sarcoma viral oncogene homolog (KRAS) variants [glycine-to-cysteine substitution at codon 12 (G12C), glycine-to-aspartic acid substitution at codon 12 (G12D), and active GTP-bound RAS (RAS(ON)) inhibitors; degraders; and chimeric antigen receptor T-cell (CAR-T)], methylthioadenosine phosphorylase (MTAP) loss (methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A) inhibition), tumor protein p53 (TP53) tyrosine-to-cysteine substitution at codon 220 (Y220C) allele-specific reactivation, and fibroblast growth factor receptor 2 (FGFR2) and neuregulin (NRG) fusions. We explore critical challenges including standardized assays, endpoints, infrastructure, and access limitations. Finally, we outline features shaping next-generation programs: novel basket-trial designs, real-world evidence integration, and international collaborative frameworks. With molecules, infrastructure, and trial designs advancing in parallel, tumor-agnostic strategies are poised to deliver equitable benefit across cancers, realizing precision medicine without borders.

Cancer cachexia involves more than a caloric deficit. A recent study by Cross et al. in Science shows that dietary lipid composition exacerbates cachexia in LKB1/STK11-deficient lung cancer through local prostaglandin E2 production and pulmonary sensory neuron activation. By linking local lipid metabolism to anorexia and wasting, these findings support precision nutritional interventions for cancer cachexia.

Antibody–drug conjugates have long been designed as fixed therapeutic entities. In Nature, Simó et al. introduce in vivo molecular assembly as an alternative strategy, prompting a broader question: could future cancer therapeutics be engineered by programming molecular interactions within patients rather than constructing increasingly complex drugs beforehand?

Oncogenic fusions both drive hematologic cancers and enable precise measurable residual disease tracking, yet whether residual fusion products can be therapeutically controlled remains incompletely defined. Emerging genomic, RNA, and proteostasis strategies now frame fusion control as a layer-matched therapeutic strategy.

Tumors co-opt normal wound-healing programs to shape their immune microenvironment, yet how distinct immune states arise and influence therapy remains unclear. Here, we synthesize emerging evidence that tumors become locked in either proinflammatory or pro-resolution phases, defined by neutrophil- or macrophage-dominated ecosystems. These states not only remodel local tissues but also systemically reprogram hematopoiesis, creating self-reinforcing immune circuits that drive progression, metastasis, and treatment resistance. We highlight recent advances linking epithelial–mesenchymal plasticity, lipid metabolism, and myeloid dynamics into an integrated ‘wound-healing clock’ model. This framework provides a conceptual basis for patient stratification and suggests that therapeutically redirecting immune states may unlock new strategies to overcome resistance across cancer types.

The role of adaptive mRNA structures in regulating gene expression in mammalian cells remains poorly understood. Synonymous mutations have been linked to a range of diseases, including cancer, yet their impact on cell biology remains largely unexplored. This opinion focuses on how cancer-associated synonymous mutations (CASMs) in the TP53 mRNA disrupt signal-induced mRNA structures and alter the activity of the encoded protein. CASM203 induces conformational changes that recapitulate those driven by PERK during the unfolded protein response, promoting expression of the p53/p47 isoform. By contrast, CASM22 and CASM34 interfere with DNA damage-induced RNA structures and affect full-length p53 activity. Together, these examples illustrate an underappreciated regulatory axis in which dynamic mRNA structures interface between upstream signalling pathways and downstream effector functions, with direct implications for tumour biology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein–protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

Metastatic heterogeneity has traditionally been explained by tumor-intrinsic evolution. A recent study by Peng-Winkler et al. challenges this paradigm by demonstrating that hepatic steatosis instructs colorectal cancer liver metastasis through fatty acid-dependent myelocytomatosis oncogene protein (MYC) activation. These findings identify host metabolism as an independent determinant of metastatic fate and suggest that precision oncology should extend beyond tumor genomics.

RNA-binding motif protein 15 (RBM15) is a key regulator of hematopoiesis and leukemogenesis, linking RNA metabolism, epitranscriptomic regulation, and lineage specification. Identified through the RBM15::MKL1 fusion in acute megakaryoblastic leukemia (AMKL), RBM15 functions within the N6-methyladenosine (m6A) writer complex, where its RNA-recognition motifs and Spen paralog and ortholog C-terminal domain enable site-specific methylation and protein recruitment. In hematopoietic stem and progenitor cells, RBM15 supports stem cell quiescence, self-renewal, and balanced lineage output, with additional roles in B cell, myeloid, and megakaryocytic differentiation. Mechanistically, RBM15 links m6A deposition to chromatin regulation, RNA export, and splicing. This review summarizes RBM15 structure, function, and regulation and highlights its emerging roles in leukemia, including AMKL and myelodysplastic syndromes, while outlining key questions for future studies.

Rare cancers collectively account for approximately a quarter of diagnosed cancers. However, these tumors remain understudied due to research constraints, including underfunding, scarce samples, and reliance on resource-intensive mouse models. We propose a Zebrafish-First Triage Strategy to screen potential therapeutic targets before mammalian validation and accelerate research and drug development.

Tumors represent a heterogeneous set of neoplastic diseases, each composed of an intricate network of cancer cells residing in multiple alternative phenotypic states. Transitions between these phenotypic states, often termed ‘phenotypic plasticity’, enable them to execute specific steps in tumor progression and to develop therapeutic resistance. The phenotypic plasticity of tumor cells is mediated, in part, by cellular processes that orchestrate normal embryonic development and are hijacked by tumors. In this review, we discuss the contributions of these developmental programs to cancer cell phenotypic plasticity. We focus on epithelial–mesenchymal transition and ciliogenesis programs and discuss new insights into the mechanistic roles of these cellular processes in cancer progression and response to treatment.

Targeting transcription factor fusion-positive cancers has proven challenging for decades. In SARC037, Grohar et al. show that histology-specific dosing of trabectedin and low-dose irinotecan is active in advanced Ewing sarcoma and downregulates EWSR1::FLI1 activity.

Prostate cancer (PCa) remains one of the most prevalent and lethal cancers in men, particularly in its metastatic form. Despite therapeutic advancements, resistance to therapy often leads to a castration-resistant state with genetic and molecular alterations that promote immune evasion and disease progression. Chronic inflammation and the immunosuppressive tumor microenvironment (TME) further exacerbate immune dysfunction. The suboptimal clinical success of current immunotherapies in advanced PCa underscores the urgent need to better understand the mechanisms underlying immune escape during disease progression and in response to therapeutic interventions. This review explores the key immune-evasive features of PCa, the contribution of the TME, and the immunotherapeutic strategies that have been clinically evaluated to improve outcomes in patients with advanced disease.

Desmoplastic stroma defines pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. This stroma drives tumor progression, immune evasion, drug resistance, and poor drug delivery. Although targeting tumor stroma has shown preclinical promise, most clinical trials have failed due to limited translational success. A major hurdle is the stroma’s extreme heterogeneity and dynamic nature, meaning uniform treatments fail. Emerging evidence supports the existence of distinct ‘stromal states’ with differential biological functions and therapeutic vulnerabilities. Characterizing these states provides a framework to stratify patients and guide precise, stroma-directed therapies. This review summarizes the clinical landscape of PDAC stroma-targeting strategies, discusses distinct stromal states, and outlines emerging opportunities to exploit the stroma as a therapeutic axis in PDAC to improve clinical trial outcomes.

By positioning phase separation between Kirsten rat sarcoma virus oncogene homolog (KRAS) lipidation and membrane signaling, Wang et al. unify distinct aspects of KRAS biology. They show that farnesylation drives cytoplasmic KRAS condensates that promote processing, trafficking, and signaling, establishing condensat formation as a new mechanism for controlling RAS activity.

In a recent study published in Cell Press Blue, Huang et al. show that deubiquitinase-dependent stabilization of POU2F3 (POU class 2 homeobox 3), primarily driven by USP2 (Ubiquitin-Specific Protease 2), sustains the growth of the small cell lung cancer (SCLC)-P subtype of SCLC, revealing a strategy to exploit transcription factor dependence by disrupting protein stability.

Targeting RNA-binding proteins has been shown to be challenging due to the absence of druggable pockets. Recently, Lu et al. identified a molecular glue capable of degrading HuR and suppressing BRAF-mutant colorectal cancer. These findings offer a promising therapeutic pathway for the treatment of a subset of HuR-driven malignancies.

Cancers containing histologically distinct cell populations could arise from multiple transforming events, from transdifferentiation late in tumor evolution, or from a single progenitor cell. Poulain and colleagues show that glandular and squamous cells in adenosquamous carcinomas caused by human papillomavirus infection are descendants of a common ancestor.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies; however, their efficacy in solid tumors remains limited by therapy resistance. This resistance arises from the metabolic reprogramming of immune cells in the tumor microenvironment (TME), a metabolic ‘cage’ where immune and cancer cells compete for nutrients. Immune effector cells succumb to metabolic exhaustion amid nutrient competition, whereas immunosuppressive cells augment inhibitory functions via metabolic adaptation, collectively mediating tumor immune evasion. This review systematically delineates the metabolic reprogramming features of immune cells in the TME, dissects the molecular mechanisms governing ICI resistance, and summarizes combination strategies targeting metabolic pathways to reverse resistance, providing theoretical and translational insights for optimizing cancer immunotherapy.

Frontline treatments for mantle cell lymphoma were historically dictated by age and fitness for intensive chemoimmunotherapy and autologous stem cell transplantation. While yielding high response rates, these approaches are associated with treatment-related morbidity and disease relapse. The therapeutic landscape is trending toward biological precision. This review highlights the timely frontline integration of novel targeted agents that directly challenge the need for traditional consolidative transplants while de-escalating or even sparing chemotherapy. Measurable residual disease is increasingly used to identify early relapses and inform the duration and individualization of therapy. By integrating targeted and immune-engaging therapeutics with optimized maintenance to deepen responses and prolong survival, these advancements aim to maximize long-term remission while minimizing toxicity.

In clonal hematopoiesis (CH), hematopoietic stem cells (HSCs) with mutations conferring a fitness advantage preferentially expand under evolutionary constraints. Over the last decade, cancer therapy has emerged as a selective pressure contributing to high rates of CH in patients with hematological and nonhematological cancers. Distinct chemotherapies, radiotherapies, immunotherapies, and targeted cancer therapies shape somatic evolution by inducing de novo mutations and by conferring a selective advantage to pre-existing CH clones. Such expansion may influence treatment response and toxicity, and is linked to the development of therapy-related myeloid neoplasms. CH prevalence will continue to increase as treatment options expand, cancers are detected earlier, and patients live longer. Managing CH and its adverse effects has the potential to improve cancer outcomes and survivorship.

While breast cancer (BC) has always been considered an immunological ‘cold’ tumor type, anti-programmed cell death protein 1 (PD-1) has recently changed the treatment landscape of triple-negative breast cancer, and neoadjuvant Phase III trials for high-grade estrogen receptor-positive breast cancer have reported promising results. However, a substantial number of patients do not benefit and are in need of novel combination strategies. In addition, since anti-PD-1 is added to combination chemotherapy, there is a growing issue of overtreatment for patients with an already excellent outcome. In this review, we discuss the status and challenges of neoadjuvant immunotherapy in BC, including the need for prognostic and predictive biomarkers to guide treatment individualization and optimize the balance between the efficacy and toxicity of immunotherapy.

Microbial metabolites can act as systemic signals that connect gut dysbiosis to tumor immune remodeling. Recently, Li et al. showed that gut microbiota-derived deoxycholic acid activates the farnesoid X receptor–nuclear factor κB–interleukin-6 axis in breast cancer cells, promoting the recruitment of granulocytic myeloid-derived suppressor cells, T helper polarization, and tumor progression. These findings offer new insights into microbial bile acid signaling in the tumor microenvironment.

Sensory nerves are emerging as regulators of tumor immunity. A newly identified Nav1.8+ neuron–calcitonin gene-related peptide axis in lung adenocarcinoma links nociceptive signaling to impaired tertiary lymphoid structure formation and immune escape, suggesting that neural checkpoint blockade may help remodel immune-cold tumors and improve immunotherapy responses (Ho et al.).

Autophagy underlies several immunosuppressive mechanisms that collectively endow cancer cells with prominent immunoevasive features. Recent data from Hoslett et al. demonstrate that a specialized variant of autophagy commonly known as nucleophagy actively removes PARP1 molecules trapped on DNA upon pharmacological inhibition, mediating robust cytoprotective and possibly immunosuppressive effects.

Neuroendocrine carcinomas, including small cell lung cancers, are notable for their immune desert phenotype, even with the addition of immunotherapies. While this has been attributed to absent antigen presentation, Wang and colleagues demonstrate the existence of a vascular barrier that limits T cell infiltration and physically underlies this phenotype.

Neuron–tumor communication is emerging as a distinct layer of tumor–host interaction beyond conventional stromal, vascular, and immune regulation. Recent studies show that malignant cells can detect neuronal activity and convert neural signals into growth-promoting cellular responses. In the brain, glioma cells can become electrically integrated into neuronal circuits, where glutamatergic input drives depolarization, calcium influx, and downstream signaling. In extracranial tumors, neural influence appears more heterogeneous, involving spatially organized neurochemical niches, receptor-enriched cancer–nerve contacts (‘pseudo-synapses’), autonomic pathways, and injury-associated neuroimmune remodeling. These findings raise important questions about how neural input regulates tumor cell state, metabolism, immune tone, and therapeutic adaptation. This review evaluates the evidence linking neural activity to cancer progression across anatomical contexts and outlines the experimental standards needed to distinguish structured neuron–tumor interfaces from broader neural effects within the tumor microenvironment.

Itaconate (ITA) is an endogenous metabolite produced from cis-aconitate by the immune-responsive gene 1-encoded enzyme aconitate decarboxylase 1 and has emerged as an important immune-metabolic regulator in cancer. In the tumor immune microenvironment, endogenous ITA is increasingly associated with an immunosuppressive microenvironment, tumor cell immune evasion, and therapeutic resistance, supporting a predominantly pro-tumor role in vivo. Nevertheless, the field remains clouded by several unresolved issues, including the heavy reliance on a limited number of tumor models, the persistent conflation of endogenous ITA with membrane-permeable derivatives, the incomplete definition of the mechanisms underlying its intercellular effects, and the uncertain cross-species relevance of current findings. Here, we highlight recent evidence supporting the physiological functions of endogenous ITA in cancer, delineate major boundaries and ambiguities in current interpretation, and outline key questions that should guide future mechanistic and translational studies.

Hematologic patient-derived organoids (PDOs) reconstruct human bone marrow and lymph node microenvironments in 3D, preserving malignant cell states, clonal diversity, and clinically relevant drug responses. Leukemia PDOs artificially mimic the complex bone marrow niche and cytokine dependencies. Lymphoma PDOs recapture immune–stromal interactions and enable testing of targeted and immunotherapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cells. Multiple myeloma PDOs model the bone marrow microenvironment and maintain plasma tumor cell survival cues that drive drug resistance. Across preclinical models, PDOs outperform 2D cultures, spheroids, and xenografts in mechanistic and translational resolution. Converging regulatory support and National Institutes of Health investment position hematologic PDOs as frontline platforms for functional precision oncology. This review highlights current systems, disease-specific advances, quality standards, and future directions.

Extracellular vesicles (EVs) are increasingly recognized as minimally invasive sources of molecular information in cancer, carrying nucleic acids, proteins, lipids, and metabolites that reflect tumor biology. Recent advances in high-throughput sequencing and mass spectrometry have not only enabled multi-omics profiling of EV cargo but also revealed that different molecular layers capture distinct yet complementary aspects of cancer processes. This review provides a comprehensive overview of the rapidly expanding landscape of EV multi-omics, highlighting methodological constraints, the predominance of proteo-transcriptomic analyses, and the principal strategies used for multi-omics layer data integration. We outline how these developments refine biomarker discovery, expose new mechanistic insights, and emphasize the need for standardized, multi-analyte EV workflows to fully realize their clinical and translational potential.

Molecular profiling is central to pediatric precision oncology, yet only 15–20% of patients benefit from biology-guided treatments. This limitation underscores the urgent need for functional precision medicine, which interrogates therapeutic vulnerabilities using patient-derived models. Despite hurdles in establishing these models, such as limited biopsy material and technical screening barriers, recent advances in tumoroids, patient-derived xenografts and high-throughput platforms offer an unprecedented opportunity to bridge the translational gap. In this review, we describe the evolution of patient-derived models of pediatric brain cancers, their current strengths and weaknesses and the technological innovations redefining the field. Together, these insights provide a road map for integrating functional data into clinical decision-making, ultimately aiming to ‘cure more and heal better’ children with brain tumors.

Cancer cachexia, responsible for up to 30% of cancer deaths, has transitioned conceptually from a mere nutritional deficit into a highly coordinated, multi-organ immunometabolic network that systematically dismantles host homeostasis. This review synthesizes the paradigm-shifting discoveries that position the immune system as the central conductor of tissue wasting. We delineate how redundant inflammatory cascades, neuro–immune circuits, and local cellular plasticity converge to drive muscle and adipose catabolism. Furthermore, we dissect the metabolic competition for nutrients between tumor cells and host immunity, which accelerates structural degradation. Finally, we highlight how single-cell multiomics, spatial transcriptomics, and artificial intelligence are redefining clinical stratification, shifting the therapeutic horizon toward individualized, multi-node immunometabolic interventions, thereby providing a theoretical framework for the management of cachectic wasting syndrome.

The Drug Rediscovery Protocol by K. Verkerk, et al., operationalized nationwide biomarker-guided, off-label precision oncology. Yet outcomes (15.7% response rate) mirror a decade of studies, indicating a single biomarker–drug strategy ceiling. Advancing efficacy will require customized, individualized combinations, consistent with the hallmarks of cancer complexity and the I-PREDICT (Investigation of profile-related evidence determining individualized cancer therapy) style clinical studies framework, which shows that outcomes scale with greater biomarker matching.

Horizontal mitochondrial transfer (HMT) is an emerging field of cell biology. Since its discovery, HMT has been extensively studied in the context of cancer due to the essential role of mitochondria in fueling the proliferation of tumor cells. The role of HMT in cancer, however, reaches far beyond a simple mechanism of organelle acquisition. Indeed, several recent studies have demonstrated HMT from cancer to immune cells and vice versa, with a profound impact on antitumor immune responses and potentially on immunotherapy efficacy. In this opinion article, we propose that HMT should receive attention as another modulatable mechanism of the functional tug-of-war between cancer and immune cells, further contributing to the complexity of the tumor microenvironment and likely sculpting the outcome of competition between the two teams of cells.

Heart cancer or metastasis is very rare, yet the heart is highly vascularized and mechanically pumps blood flow through our body. Recent findings from Ciucci et al. show that mechanical load in the beating heart suppresses cancer growth via Nesprin-2-dependent mechanotransduction, which changes histone methylation and chromatin compaction to keep proliferation genes less active in cardiac tumor cells.

Aging is a major risk factor for cancer, yet its role in cancer biology remains largely unexplored and often overlooked. Interestingly, studies assessing the impact of aging on oncogenic KrasG12D-driven lung tumor initiation, early progression, and metastasis have reported both pro- or antitumoral effects, which are presented and discussed herein.

Tumors are ecological systems shaped by continuous exchange with surrounding cells. The transfer of functional mitochondria, which reprograms malignant behavior, introduces a distinct layer to this ecology. Cancer evolution may proceed not solely through mutation and selection but also through the horizontal assimilation of organellar traits acquired from neighboring cells.

Early-life exposure to both modifiable and nonmodifiable risk factors may induce chronic low-grade inflammation (CLGI), a silent threat potentially driving the rising incidence of early-onset colorectal cancer (EOCRC). Notably, CLGI could promote EOCRC by altering the proinflammatory and immune microenvironment that supports tumor growth and cancer development. In this review, we examine how risk factors disrupt immune homeostasis and contribute to CLGI in young individuals, thereby promoting the development of EOCRC. Additionally, identifying CLGI-specific biomarkers could aid in early detection and diagnosis, while targeting specific molecular pathways may enable personalized therapeutic interventions for EOCRC by reducing the chronic inflammatory threat. We also highlight the importance of lifestyle changes and interventions to reduce CLGI and address the growing health concern of EOCRC.

Chromosomal rearrangements leading to the formation of fusion oncoproteins (FOs) are drivers of leukemia and other cancers. Many such FOs are now known to localize in nuclear or cytoplasmic condensates formed through the process of phase separation (PS). FO-associated condensates facilitate the spatiotemporal organization of key macromolecules required for oncogenic transformation. NUP98 fusions provided the first example of FO-associated condensates in leukemia, and other leukemic drivers subsequently illustrated the shared and distinct mechanisms by which PS contributes to leukemogenesis. Improved understanding of FO-associated condensates has, in turn, revealed new opportunities for therapeutic targeting. Pharmacologic approaches, including the dissolution of condensates, inhibition of key condensate components, or modification of condensate material properties, may translate to more effective treatments for patients with FO-driven cancer.

Pseudomyxoma peritonei is a rare, heterogeneous appendiceal cancer characterized by mucus-secreting tumor cells. Evidence suggests a microbial association, though its significance remains unclear. This forum article synthesizes links among microbial communities, mucin biology, and tumor behavior, highlighting key research challenges and how spatial multiomics may clarify disease mechanisms and therapeutic opportunities.

Aging is the first risk factor associated with cancer, predominantly due to cumulative somatic mutations and a profound decline in antitumor immunity. The aging process remodels immune function across hematopoietic, adaptive, and innate compartments through interconnected processes, including hematopoietic stem cell dysfunction, loss of metabolic fitness, altered B and T cell phenotypes, myeloid skewing, and a complex interplay between cellular senescence and inflammaging. These changes collectively establish an immunosuppressive landscape that weakens natural tumor surveillance and constrains responses to cancer immunotherapies. Given the shift toward an aging global population and the disproportionate cancer burden in older individuals, we emphasize the clinical relevance of patient-stratification strategies. We further discuss emerging approaches aimed at rejuvenating immune function to improve immunotherapy outcomes in older patients.

Biliary tract cancers have a poor prognosis, with tumor location and desmoplasia often restricting tissue acquisition for molecular profiling. Circulating tumor DNA is a minimally invasive alternative with expanding clinical utility, although technical and standardization challenges limit its routine adoption. We review evidence, limitations, and strategies supporting large-scale validation for real-time monitoring and personalized treatment.

The essential role of β-catenin/CTNNB1 in cell development highlights its therapeutic potential in cancer and neurodevelopmental syndromes. Opposing functional alterations of β-catenin in these diseases reflect distinct pathogenic genetic events in CTNNB1, leading to antagonistic therapeutic approaches. A comprehensive understanding of β-catenin functions in physiology and pathology will facilitate the implementation of β-catenin/CTNNB1-based therapies.

The gut microbiome exerts distant and local effects on tumours, healthy epithelial cells, and the immune system through the production of bioactive metabolites. This influences cancer therapy responses across treatment modalities and cancer types. In this review, we discuss promising approaches to boost beneficial microbiota-derived metabolites to enhance existing cancer therapies, including prebiotics, probiotics, postbiotics, and live biotherapeutic products. Each approach faces challenges in achieving physiological concentrations and tissue distribution, as well as different regulatory regimes and commercial landscapes. With promising early clinical trials and significant scientific and commercial activity in these areas, there is hope that targeted, metabolite-focused interventions will soon benefit cancer patients.

With immune checkpoint inhibitors (ICIs) being an established therapeutic pillar for many cancers, the management of their associated toxicities has emerged as a key clinical challenge. Immune-related adverse events (irAEs) frequently require immunosuppressive therapy, raising the concern that these treatments may dampen the antitumor effects elicited by ICIs. Foundational work in mice enabled the discovery of ICIs, and in this review, we discuss the continued importance of preclinical mouse modeling to understand the molecular mechanisms underpinning the most common irAEs. Mouse models can be used as surrogates to evaluate the effects of immunosuppressive therapies on irAEs, tumor growth, and ICI-mediated antitumor immunity. In reviewing genetic and pharmacological approaches to induce irAEs in mice, we identify key considerations for developing next-generation mouse models of irAEs.

Epithelial–mesenchymal transition (EMT) in breast cancer is better understood as epithelial–mesenchymal plasticity (EMP), a dynamic and reversible spectrum of epithelial, hybrid, and mesenchymal states. In this review, we discuss how EMP is deployed differently across hormone receptor-positive/HER2-negative, HER2-positive, and triple-negative/claudin-low breast cancers, with distinct implications for metastasis, immune evasion, liquid biopsy, and therapeutic resistance. We highlight the regulatory networks and microenvironmental cues that shape state transitions and emphasize that hybrid and plasticity-high states may be more clinically informative than terminal mesenchymal states alone. We propose that progress will depend on subtype-aware, biomarker-guided strategies that resolve carcinoma cell state in space and time and therapeutically exploit EMT-associated vulnerabilities.