A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer

Zheng et al. identify a PIKfyve-ER stress-lipogenesis axis that enables neuroendocrine prostate cancer cells to tolerate elevated basal ER stress through PIKfyve-dependent lysosomal homeostasis and SREBP-driven lipogenesis. Dual inhibition of PIKfyve and FASN disrupts these adaptive pathways, driving terminal UPR activation and apoptosis and providing a robust translational strategy.

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Mapping micrometastatic seeds of relapse

In this issue of Cancer Cell, Liu et al. apply spatial multi-omics to map colorectal cancer micrometastases across primary tumors and matched liver and lung metastases, revealing liver micrometastases as an early evolved, stem-like, immune-suppressed residual disease state linked to a six-gene recurrence signature.

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Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy

Mallard de La Varende et al. demonstrate that gut dysbiosis impairs tumor immunosurveillance through the gut-liver axis, causing subclinical cholestasis and immunotherapy resistance in tumors distant from gastrointestinal and hepatic tissues. Gut dysbiosis triggers plasma elevation of γ-glutamyl transferase, increase in TCDCA in humans (TMCA in mice), and drop in sMAdCAM-1 levels.

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Depletion of an immature cord blood NK subset reverses trogocytosis-driven CAR NK dysfunction

Li et al. identify a previously unrecognized NK cell subset that limits cord blood-derived CAR-NK cell therapy by diverting tumor targeting and promoting self-directed fratricide and show that donor cell composition shapes efficacy while offering a practical manufacturing strategy to improve consistency, persistence, and antitumor activity of off-the-shelf CAR-NK therapies.

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Dysbiosis-associated bile acids slam the brakes on immune checkpoint therapy

Antibiotics compromise the efficacy of immune checkpoint inhibition (ICI) therapy in cancer, but the underlying mechanism remains unclear. In this issue of Cancer Cell, Mallard de La Varende et al. identify dysbiosis-associated tauro-conjugated bile acids as drivers of ICI non-response and γ-glutamyl transferase (γGT) as a predictive biomarker.

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Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies

Meyerhoff et al. identify tumor-infiltrating plasma cells as a source of antibodies with therapeutic potential. Their lead antibody, PC-1, recognizes citrullinated antigens on cancer and tumor-promoting myeloid cells and can be repurposed to guide CAR T cell therapy.

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Tumor-infiltrating plasma cell targets as a source for immunotherapies

Tumor-infiltrating plasma cells are key responders to immunotherapy. In this issue of Cancer Cell, Meyerhoff et al. show that plasma cells from lung lesions of anti-PD-1-treated patients target citrullinated proteins. Engineering CAR T cells with these plasma cells scFv reveals anti-tumor specificity without adverse effects, identifying therapeutic opportunities.

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A self-amplifying nerve-fibroblast circuit drives colorectal cancer progression

Kobayashi et al. demonstrate that cholinergic signaling induces NTN1 secretion from colorectal CAFs, which in turn enhances intratumoral cholinergic innervation. Increased acetylcholine and CAF-derived NTN1 then accelerate cancer cell growth through tumoral CHRM3 and UNC5B. Blocking CHRM3 or NTN1 may represent a promising therapeutic approach for CRC.

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Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

(Cancer Cell 35, 633–648.e1–e7; April 15, 2019)

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CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

(Cancer Cell 31, 653–668.e1–e7; May 8, 2017)

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Bile Acid and Inflammation Activate Gastric Cardia Stem Cells in a Mouse Model of Barrett-Like Metaplasia

(Cancer Cell 21, 36–51; January 17, 2012)

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PD-1 blockade unleashes local hepatitis B virus-related B cell response inhibiting hepatocellular carcinoma

Following perioperative anti-PD-1 therapy in hepatocellular carcinoma, Chen et al. report two distinct subtypes of late-recurrence patients characterized by either T cell or B cell dominant responses within tumors. Through single-cell spatial transcriptomics and antibody cloning experiments, they show that anti-PD-1 induces local HBV-targeted antibody responses and complement-mediated anti-tumor activity.

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Perioperative tislelizumab plus chemotherapy for locally advanced gastric cancer: A randomized, prospective phase 2 trial

Xu et al. report a biomarker-stratified, randomized, multicenter phase 2 trial of perioperative immunochemotherapy in patients with tumor-specific (ts)MHC-II-positive or -negative gastric/gastroesophageal junction cancer (GC/GEJC). Perioperative immunochemotherapy significantly improved the major pathologic response (mPR) rate only in tsMHC-II-positive patients, with no comparable benefit in the tsMHC-II-negative group, supporting tsMHC-II as a predictive biomarker for selecting patients for perioperative immunotherapy.

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The Terry Fox Research Institute Marathon of Hope Cancer Centres Network: A pan-Canadian precision oncology initiative

(Cancer Cell 43, ▪▪▪–▪▪▪; April 14, 2025)

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Starved of oxygen and fueled by macrophages: Path to progression in RCC

In this issue of Cancer Cell, Vuong et al. perform a cross-species functional and molecular analysis of the mechanisms of response and adaptation to VEGFR kinase inhibitors and immunotherapy, identifying SPP1+ tumor-associated macrophages as key players of response to therapy. They further demonstrate that chronic treatment promotes metastatic spread.

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OpenIO: An open framework for AI-native immunotherapy

We propose Open Immune Oncology (OpenIO), a framework integrating generative AI and omics to advance precision oncology. By leveraging biological scaling laws and foundation models, we aim to transition immunotherapy from empirical screening to rational, AI-native engineering of therapeutic interventions.

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Intratumoral B cells under stress

In this issue of Cancer Cell, Bashir et al. show that stress-induced corticosterone suppresses germinal center B cell responses and impairs anti-tumor immunity. Their study identifies gut microbiota-derived phage DNA as a key trigger of TLR9 activation and corticosterone secretion by cancer-associated fibroblasts, revealing an intricate bacteria-driven immune-suppression mechanism.

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Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts

In this review, Liu et al. propose a unifying framework that organizes cancer-associated fibroblasts into conserved molecular phenotypes and spatial archetypes. By linking cellular lineage, tissue context, and function, this model clarifies stromal heterogeneity and provides a foundation for developing precision strategies to selectively target pathogenic tumor-promoting stroma.

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Chronic stress unleashes an intratumor phage-fibroblast-B cell circuit to promote tumor growth

Bashir et al. show that chronic stress disrupts the gut barrier, enabling Enterococcus gallinarum translocation to tumors. There, Eg phage DNA activates cancer-associated fibroblasts via TLR9 to produce local glucocorticoids that suppress germinal-center B cell responses and accelerate tumor growth. Targeting this phage-CAF-B cell circuit restores anti-tumor immunity.

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Context dependency in cancer neuroscience

Neural signaling shapes tumor progression, but it is not intrinsically tumor-promoting or tumor-restrictive. Birbrair et al. argue that neural directionality is context-dependent and governed by tumor kinetics, tissue architecture, neural state, receptor and target-cell topology, immune-host biology, and treatment history. They propose a mechanistically interpretable and clinically actionable reporting framework for precision neuromodulatory oncology.

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Targeting drug-tolerant persister cells: Let’s bring on the TROPs!

In this issue of Cancer Cell, Liao et al. identify TROP2 as an EGFR tyrosine kinase inhibitor-induced vulnerability in drug-tolerant persister lung cancer cells. They show that anti-TROP2 antibody-drug conjugates target this residual population, supporting an “induce-target-kill” strategy to delay resistance and extend the benefit of EGFR tyrosine kinase inhibition.

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Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell lung cancer

Liao et al. show that EGFR tyrosine kinase inhibitor treatment relieves c-Myc-mediated transcriptional repression of TROP2 and upregulates its expression in drug-tolerant persister cells in non-small-cell lung cancer (NSCLC). A TROP2-targeting antibody-drug conjugate combined with osimertinib suppresses persister cells, delays relapse, and shows promising preliminary clinical activity.

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STING unlocks CD4⁺ T cell immunity in pancreatic cancer

Pancreatic ductal adenocarcinomas (PDACs) are lethal cancers resistant to immunotherapies. In this issue of Cancer Cell, Kureshi et al. show that combining checkpoint blockade with STING-mediated innate immune stimulation unlocks cDC2-driven CD4+ T cell immunity in mice, promoting PDAC immune control. This cellular axis may be exploited for PDAC therapy.

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Attack of the clones: Tracing the dynamics of innate immune cells in human cancer

In this issue of Cancer Cell, Liu et al. use mitochondrial DNA mutations to reconstruct clonal lineages of the innate immune compartment in human tumors. They show that intratumoral type 3 dendritic cells (DC3s) arise from circulating monocytes and that a monocyte’s fate in the tumor microenvironment is programmed peripherally, prior to tissue entry.

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The cartography of KRAS inhibitor resistance in colorectal cancer

In this issue of Cancer Cell, Alonso et al. demonstrate that in patients with advanced colorectal cancer, there are regionally distinct genomic and transcriptomic adaptive responses to KRAS G12C inhibition, including epithelial cell state changes and pro-inflammatory pathway enrichment, and provide insights into key resistance mechanisms to KRAS G12C inhibition.

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An epigenetic four-lane route to camouflage for cancer cells

Malignant cells can exploit numerous mechanisms to evade anti-tumor immunity. In this issue of Cancer Cell, Foidart et al. demonstrate that neoplastic cells undergoing whole-genome doubling acquire epigenetic changes that actively suppress antigen presentation, hence effectively hiding from recognition and elimination by CD8+ T lymphocytes.

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High-plasticity oncofetal cell states in early pre-metastatic colorectal cancer

In Nature, Buissant des Amorie et al. demonstrate that colorectal cancer acquires oncofetal cell states that resemble embryonic intestines, confer stem-like features, reshape epithelial identity, and prime cells for invasion and metastasis. Oncofetal cells are essential for metastasis and ubiquitous in non-metastatic tumors, with cancer-associated fibroblasts as key microenvironmental drivers.

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Pathogenesis of diffuse large B cell lymphoma proteogenotypes

Enssle et al. perform transcriptomic and proteomic profiling of diffuse large B cell lymphoma (DLBCL), revealing seven proteogenotypes (PGs) that reflect molecular and tumor microenvironment features across genetic DLBCL subtypes. PG4 identifies high-risk DLBCLs with diverse mutational profiles characterized by enhanced MYC and B cell receptor activity and exhausted T cells.

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Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma

Vuong et al. comprehensively profile the tumor microenvironment in mouse and human ccRCC after VEGFR-TKI and ICI therapy to reveal that SPP1+ TAM recruitment reflects true tissue hypoxia and acts as a biomarker of response. Furthermore, chronic treatment exacerbates metastases in mice, highlighting the potential adverse effects of sustained hypoxia.

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Clonal lineage tracing of innate immune cells in human cancer

Liu et al. develop Mitotrek, a method that uses single-cell multi-omics with mitochondrial DNA clonal tracing to map the clonal origins of innate immune cells in human tumors. They reveal that tumor myeloid populations arise from circulating monocytes with pre-existing epigenetic fate biases, suggesting that tumor immunity is shaped before tumor infiltration.

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