Cancer Cell

Tumor-restraining fibroblasts emerge after chemotherapy specifically in responders In this issue of Cancer Cell, Ma et al. identify a neoadjuvant chemotherapy-induced population of PTGER3+ cancer-associated fibroblasts (CAFs) in patients with bladder cancer.1 These CAFs undergo lipid oxidation reprogramming and enhance CD8+ T cell function, facilitating tumor microenvironment remodeling and restraining tumor progression.

Online Now: Tumor-restraining fibroblasts emerge after chemotherapy specifically in responders

Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer Integrating microphysiological and spatial profiling, Campisi et al. identify tumor vasculature as a major barrier to NK cell recruitment in SCLC. Activating vascular STING signaling restores NK cell trafficking and cytotoxicity, enhancing response to DLL3-targeted CAR NK therapy. Their work provides a strategy to model and enhance NK cell therapies for solid tumors.

Online Now: Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer

A closed tumor-immune-brain circuit in cancer cachexia Cancer-associated cachexia is a complex metabolic syndrome leading to sustained body weight loss and tissue wasting. In this issue of Cancer Cell, Shi et al. identify a novel GDF15-driven tumor-immune-brain crosstalk, resulting in altered systemic metabolism and tissue catabolism.

Online Now: A closed tumor-immune-brain circuit in cancer cachexia

HS-20093, a B7-H3-targeted antibody-drug conjugate in lung cancer: Results from the ARTEMIS-001 phase 1a/b trial Wang et al. conducted an open-label, multicenter phase 1a/b study to evaluate the safety, pharmacokinetics, and efficacy of HS-20093 in patients with advanced solid tumors. HS-20093 demonstrated a manageable safety profile and promising antitumor activity, especially in patients with heavily pretreated lung cancer.

Online Now: HS-20093, a B7-H3-targeted antibody-drug conjugate in lung cancer: Results from the ARTEMIS-001 phase 1a/b trial

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Structuring pathology foundation models with domain knowledge In this issue of Cancer Cell, Zhou et al. present KEEP, a vision-language foundation model that incorporates hierarchical disease knowledge into pre-training via a structured disease graph. The knowledge-guided learning shapes semantic representations and enables improved zero-shot and few-shot performance across multiple pathology benchmarks, with notable effects in rare cancer classification.

Online Now: Structuring pathology foundation models with domain knowledge

Detecting microbial footprints in cancer sequencing Detecting the presence of microbial organisms within the tumor microenvironment may have biomedical relevance but presents serious technical challenges. In this issue of Cancer Cell, Ghaddar et al. develop a computational framework for the reliable detection of microbes within tumoral genomic and transcriptomic data.

Online Now: Detecting microbial footprints in cancer sequencing

Overcoming functional and translational challenges of cellular immunotherapies for solid tumors Though successful in hematologic cancers, cell therapies face major barriers in solid tumors. Chen et al. review functional and translational obstacles undermining autologous and allogeneic cell-based therapies for solid tumors. They assess key impediments, contributing factors, and emerging solutions, emphasizing engineering advances and new technologies to enable next-generation cellular immunotherapies.

Online Now: Overcoming functional and translational challenges of cellular immunotherapies for solid tumors

Candida albicans synergizes with Fusobacterium nucleatum in colorectal cancer progression via the Flo9-RadD interaction How does other types of microbe like fungi influence tumor-promoting role of Fusobacterium nucleatum? In this study, Li et al. establish that commensal fungi facilitate translocation of pro-tumor bacteria across mucus barrier to drive colorectal cancer (CRC) progression, revealing a cross-kingdom collaboration between fungi and bacteria.

Online Now: Candida albicans synergizes with Fusobacterium nucleatum in colorectal cancer progression via the Flo9-RadD interaction

Intratumoral lymphatics: When less is more Lymphatic vessels assume two-faced roles in cancer, functioning as facilitators of both immune surveillance and metastasis. In this issue of Cancer Cell, Karakousi et al. establish IFNγ as a key phenotypic and metabolic switch in tumor-associated lymphatic vessels that reinforces antitumor immunity while simultaneously blocking regional metastasis.

Online Now: Intratumoral lymphatics: When less is more

Macrophages: Targets for next-generation cancer immunotherapy Tumor-associated macrophages sit at the crossroads of immune suppression and tumor destruction, prompting renewed interest in how their biology can be therapeutically redirected. Sun et al. synthesize recent advances in macrophage heterogeneity, engineering, and targeted reprogramming to highlight next-generation strategies that could turn macrophages into a powerful and versatile arm of cancer immunotherapy.

Online Now: Macrophages: Targets for next-generation cancer immunotherapy

Knowledge-enhanced pretraining for vision-language pathology foundation model on cancer diagnosis Zhou et al. Develop KEEP, a knowledge-enhanced foundation model that integrates disease knowledge into pathology vision-language pretraining. By combining medical knowledge with large-scale image-text data, the approach improves diagnostic accuracy and generalization, particularly for rare cancers, highlighting how knowledge integration advances computational pathology and AI-driven cancer diagnosis.

Online Now: Knowledge-enhanced pretraining for vision-language pathology foundation model on cancer diagnosis

Dissecting genetic and immune drivers of heterogeneous responses to neoadjuvant immunochemotherapy in gastric cancer Zhao et al. delineate genetic and tumor microenvironment shifts of gastric cancer under neoadjuvant immunochemotherapy or chemotherapy, identifying driver events of resistance, actionable targets, and a three-tier subtyping model for precision patient management.

Online Now: Dissecting genetic and immune drivers of heterogeneous responses to neoadjuvant immunochemotherapy in gastric cancer

The cellular orchestra of CAR T success In this issue of Cancer Cell, Rade et al. report a longitudinal single-cell atlas of multiple myeloma patients receiving BCMA-directed chimeric antigen receptor (CAR) T cell therapies (Ide-cell or Cilta-cel) and identifiy features linked to long-term responses, including CD4+ T cell-driven cytotoxicity, memory-biased T cell states, reduced exhaustion, and microenvironment effects.

Online Now: The cellular orchestra of CAR T success

A conserved, terminal, pro-tumor neutrophil population In this issue of Cancer Cell, Bolli et al. leverage a newly developed neutrophil analysis framework to identify CCL3 as a conserved marker for tumor-associated neutrophils (TANs) across human and murine cancers. Using complementary genetic manipulation strategies, they demonstrate that neutrophil-derived CCL3 supports pro-tumor TAN survival within hypoxic tumor niches.

Online Now: A conserved, terminal, pro-tumor neutrophil population

Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia Shi et al. delineate an interplay among tumor cells, immune cells, and the nervous system that drives cancer cachexia and anorexia. Specifically, tumor-derived CSF1 induces macrophage GDF15, which signals through the GFRAL-RET neural axis to enhance β-adrenergic activity and systemic wasting. Disrupting this feedforward loop alleviates cachexia across cancer models.

Online Now: Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia

Lipid oxidation reprogramming in cancer-associated fibroblasts enhances CD8+ T cell cytotoxicity and therapeutic response Ma et al. identify a chemotherapy-induced PTGER3+ CAF subset with increased lipid oxidation. These CAFs secrete 11-HETE which improves CD8+ T cell function by suppressing PTEN-related signaling. The abundance of this CAF subset correlates with improved therapeutic response, revealing a stromal mechanism that supports antitumor immunity.

Online Now: Lipid oxidation reprogramming in cancer-associated fibroblasts enhances CD8+ T cell cytotoxicity and therapeutic response

Chemotherapy triggers immune evasion by fostering LEPR+ Kupffer cell differentiation in liver metastases Wang et al. show that chemotherapy reprograms liver-resident Kupffer cells into LEPR+ tumor-infiltrating cells that clear immunogenic cell death signals via MerTK-dependent efferocytosis. Targeting chemotherapy-induced LEPR+ Kupffer cells restores tumor immunogenicity and overcomes chemoresistance in liver metastases.

Online Now: Chemotherapy triggers immune evasion by fostering LEPR+ Kupffer cell differentiation in liver metastases

Enhancing therapeutic outcomes with artificial intelligence for HR-positive, HER2-negative metastatic breast cancer

Ubiquitin control of cytosolic DNA sets immune responses to DNA damage In this issue of Cancer Cell, Li et al. uncover a novel SPOP-USP7-TREX1 axis that controls cytosolic DNA clearance after DNA damage, thereby gating tumor-cell-intrinsic cyclic GMP-AMP synthase (cGAS)-STING activation and response to radioimmunotherapy. Compellingly, targeting USP7 and TREX1 might sharpen patient selection and combination strategies.

Ubiquitin control of cytosolic DNA sets immune responses to DNA damage

When the methylome becomes the microscope DNA methylation patterns stratify tumors into distinct biological, prognostic, and therapeutic response features. In this issue of Cancer Cell, Sill et al. expand the Heidelberg CNS Tumor Methylation Classifier from 91 to 184 subclasses using 7,495 methylomes, enhancing diagnostic accuracy, revealing new tumor types, and making methylation-based classification more widely accessible.

When the methylome becomes the microscope

Circulating tumor DNA as a biomarker in early phase clinical trials The clinical development of novel cancer therapeutics is rapidly evolving with the integration of molecular biomarkers to advance precision medicine. Circulating tumor DNA (ctDNA) represents a versatile tool to detect targetable alterations, predict therapeutic response, monitor tumor evolution, and inform pharmacokinetic and pharmacodynamic effects. This could accelerate early phase drug development and deepen understanding of biological drivers of response and resistance. Herein, we highlight current applications and future opportunities for ctDNA as a multi-utility biomarker in early phase clinical trials.

Circulating tumor DNA as a biomarker in early phase clinical trials

Oncofetal reprogramming of malignant seeds and their ecosystem: Implications in clinical research Oncofetal reprogramming, characterized by the re-expression of fetal-specific genes and proteins in cancer, signifies a key shift in tumor biology that encompasses both malignant cells and their microenvironment, forming the oncofetal ecosystem. In this commentary, we highlight recent advances in understanding oncofetal reprogramming and explore its emerging potential as a biomarker and therapeutic target in cancer research.

Oncofetal reprogramming of malignant seeds and their ecosystem: Implications in clinical research

Mapping the inflammatory origins of lung cancer How early precursor cells and their surrounding microenvironment cooperate to drive oncogenic progression in lung adenocarcinoma (LUAD) remains elusive. In this issue of Cancer Cell, Peng et al. conducted multimodal spatial-omics to comprehensively profile precancerous lung and LUAD tissues, uncovering alveolar progenitors and proinflammatory niches that co-evolve during cancer progression.

Mapping the inflammatory origins of lung cancer

Cancer cell death: Cell-autonomous and immunogenic dimensions Galluzzi et al. discuss cell-autonoumous and immunomodulatory aspects of cancer cell death, both from mechanistic and therapeutic standpoints.

Cancer cell death: Cell-autonomous and immunogenic dimensions

Targeting STING to generate therapeutic anti-tumor immunity Fahey et al. review the effects of cGAS-STING signaling in tumor cells and different cells of the tumor immune microenvironment, and discuss how these insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor immunity in patients.

Targeting STING to generate therapeutic anti-tumor immunity

IL-36γ armored CAR T cells reprogram neutrophils to induce endogenous antitumor immunity Zuo et al. demonstrate IL-36γ armored CAR T cells reprogram neutrophils with antigen-presenting and tumoricidal functions, inducing durable antitumor efficacy in the absence of lymphodepletion through activating endogenous immune effectors, which represents a broadly applicable strategy to overcome key barriers to adoptive cell therapies for solid tumors.

IL-36γ armored CAR T cells reprogram neutrophils to induce endogenous antitumor immunity

Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma Bernardi et al. report an extensive multiomics dataset on medulloblastoma encompassing five unbiased omics layers. Unsupervised data integration revealed intertumoral metabolic heterogeneity across Group 3 medulloblastoma. Notably, lipid storage in the MYC-driven Group 3 subtype emerges as a targetable vulnerability, offering promising therapeutic avenues against these lethal tumors.

Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma

Integrative proteogenomic analysis provides molecular insights and clinical significance in gallbladder cancer Fu et al. present an integrative proteogenomic analysis of a large gallbladder cancer cohort, which uncovers ErbB2/ErbB3 genomic alterations with clinical relevance; identifies MEIS1, ACAT1, and PHGDH as potential therapeutic targets; and establishes immune and multi-omic subtypes that inform prognosis and guide treatment strategies.

Integrative proteogenomic analysis provides molecular insights and clinical significance in gallbladder cancer

Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage Li et al. show that SPOP mutations and USP7 overexpression promote TREX1 upregulation, leading to increased cytosolic DNA degradation and suppression of cGAS-STING-mediated immune activation. Targeting USP7 enhances the effectiveness of radiotherapy combined with immune checkpoint blockade, providing a new strategy to overcome resistance and improve therapy outcomes.

Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage