Patel et al. combine six spatial-omics platforms with single-cell/single-nucleus RNA sequencing across 54 neuroblastoma tumors to resolve a debate over malignant mesenchymal (MES) tumor cells. Using signatures from patient-derived xenografts, they identify MES tumor cells and show that a higher MES score predicts worse patient outcome.

Chromatin dynamics shape gastric cancer at every stage. In this issue of Cancer Cell, Wang et al. uncover a premalignant chromatin state primed for oncogenic activation alongside a pseudo-gastric subtype that hijacks acid secretion to evade antitumor immunity, revealing gastric proton pumps as a potential therapeutic target.

Wang et al. build a chromatin accessibility atlas of 650 gastric tissue samples spanning pre-cancer to advanced cancer, revealing a cancer-like epigenetic priming state in metaplasia that licenses tumor initiation. Advanced cancers segregate into three epigenomic subtypes; the pseudo-gastric subtype resists immunotherapy via FOSL2-driven H+/K+ ATPase expression that acidifies the microenvironment and suppresses CD8+ T cells—a phenotype reversed by the acid blocker vonoprazan.

Noblecourt et al. show that chemotherapy acts as an immunological adjuvant by expanding TCF1+CD8+ T cells during vaccine priming, thereby enhancing vaccine-induced anti-tumor immunity. These findings provide a rationale for combining chemotherapy, cancer vaccines, and PD-1 blockade in the clinic.

In Nature, Desharnais et al. show that in diverse mouse models, anti-PD-1 sensitivity is more closely linked to diet-microbiome-metabolite ecosystem than to obesity-associated metabolic dysfunction. Their findings reinforce body mass index (BMI) as an incomplete proxy for host biology and suggest strategies to improve anti-PD-1 efficacy without inducing obesity.

In this issue of Cancer Cell, García-Gómez et al. show that brain-seeding cancer cells exploit an MXD4-dependent proliferative pause that enables survival under stress before metastatic outgrowth. By restraining MYC and activating protective stress responses, this pause becomes an Achilles’ heel, potentially targetable to eradicate micrometastases before clinical relapse.

García-Gómez et al. identify a transient state, termed the proliferative pause, that enables the survival of micrometastases during vascular co-option by buffering organ-imposed stress. Targeting vulnerabilities associated with this state suppresses metastatic progression and relapse, revealing opportunities for preventive intervention.

Chimeric antigen receptor (CAR) T cell therapy has shown promising activity in solid tumors, yet translational progress remains limited by preclinical models that incompletely capture human tumor biology. Patient-derived organoids (PDOs) preserve key features of human tumors, including cellular heterogeneity and tissue architecture, thereby enabling functional evaluation of CAR T cell targets, next-generation approaches, resistance mechanisms, and selected safety considerations. We discuss how PDOs complement existing preclinical platforms to support CAR T cell development for solid tumors.

In this issue of Cancer Cell, Ng et al. characterize and leverage cytotoxic γδ T cells in small cell lung cancer to overcome unsuccessful checkpoint blockade immunotherapy. Engaging Vδ2+ cells with a bispecific T cell engager (BiTE) bypasses the challenge of low MHC-I expression and ineffective CD8+ T cells.

Ng et al. show that γδ T cells infiltrate SCLC and have cancer-fighting abilities. These cells can be harnessed through multiple therapeutics to kill SCLC, including through MHC-independent recognition mechanisms via BTN2A1. Notably, γδ T cell infiltration is clinically relevant in SCLC, with high levels predictive of improved outcomes with αPD-L1.

Ji et al. show that radiotherapy induces a TET2-dependent epitranscriptomic program in myeloid cells that promotes immunosuppressive M-MDSC differentiation. TET2 loss preserves caRNA m5C-MBD6 signaling, restores IRF3-IFN-I activation, generates myeloid-derived activating cells, and enhances radiotherapy-induced antitumor immunity.

Interpreting the biological and clinical significance of somatic mutations in cancer genomes remains challenging. In this issue of Cancer Cell, Hyeon et al. identify and map significantly mutated regions to protein domains and structural features, establishing a proteo-genomics framework for interpreting cancer mutations beyond genes and hotspots.

Shi et al. report the first clinical study of the selective KRAS G12D inhibitor HRS-4642 combined with the anti-PD-L1 antibody adebrelimab in heavily pretreated patients with KRAS G12D-mutant pancreatic cancer. The chemotherapy-free regimen demonstrates a manageable safety profile and preliminary antitumor activity, supporting its feasibility as a targeted strategy in this molecularly defined subset.

Emerging data indicate that immune checkpoint inhibitors can exhibit time-of-day-dependent effects in pre-clinical models. Furthermore, multiple retrospective clinical trials associate earlier anti-tumor treatment timing with improved outcomes. However, key questions remain regarding the reproducibility of these findings, the underlying mechanisms, and their clinical implications. This commentary discusses these open questions and provides an outlook on the field.

Molecular residual disease (MRD), detected via circulating tumor DNA (ctDNA) after curative-intent surgery, identifies resectable solid tumor patients at high recurrence risk, thereby enabling enriched trials with larger effect sizes and smaller samples. Yet enrichment narrows the eligible population and thus challenges conventional randomized designs. We propose an MRD Registry as an external control cohort that integrates quantitative ctDNA data with outcomes to validate ctDNA dynamics as response indicators—facilitating efficient MRD-based trial design and accelerating novel therapy development.

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, as tumors evolve faster than therapies. Resistance is ecological, not merely KRAS driven, involving overlooked players like high-grade pancreatic intraepithelial neoplasias (PanINs), peripancreatic fat, stromal mechanics, myeloid-neural circuits, metabolic rewiring, and systemic host responses. We propose precision interception targeting PanIN/intraductal papillary mucinous neoplasm (IPMN) biology, spatial-functional-proteogenomic classification beyond transcriptomics, the Heracles Protocol (measure, prime, strike, and adapt), and integrated technologies from AI pathology to exosomal delivery and CRISPR-based synergy mapping, together making PDAC more tractable.

Scherer’s century-old classification of expansive and infiltrative glioma growth remains foundational to neuro-oncology. In this issue of Cancer Cell, Hoefflin et al. use spatial RNA and protein profiling of IDH-mutant gliomas to reveal hypoxia and necrosis as organizing centers of expansive growth and white-matter tracts as guides and constraints on invasion.

Hoefflin et al. define organizational principles of IDH-mutant gliomas using multimodal spatial profiling. They identify three spatial archetypes across histological grades and reveal that brain anatomy and hypoxia represent distinct spatial organizing forces, with the white-gray matter junction acting as a functional barrier to invasion.

Biomarkers for immune checkpoint inhibitors have largely treated the tumor immune microenvironment as a fixed property. In this issue of Cancer Cell, Lin et al. assemble a longitudinal pan-cancer single-cell atlas and show that the direction of immune-state remodeling during therapy is more informative than baseline composition.

In this issue of Cancer Cell, Manca et al. investigate the genomic evolution and metastatic tropism of over 7,000 colorectal cancers. Integrating primary tumor location, genomic alterations, and clinical variables, they reveal how distinct patterns of tumor evolution shape metastatic competence and impact organ tropism, offering a framework to refine surveillance.

Manca et al. analyze >7,000 colorectal cancers, integrating next-generation sequencing and clinical data. They define tumor genomics, clonality and dosage of mutations, and metastatic tropisms and their effects on patient outcomes. Incorporating metastatic sites, primary tumor location, and genomics, they develop an organ-specific risk model for metastasis.

Lin et al. assemble a longitudinal pan-cancer single-cell atlas that tracks how the tumor immune microenvironment remodels during checkpoint inhibitor therapy. They show that the direction of remodeling, rather than the pre-treatment state, predicts response and translate these dynamics into a baseline gene signature that forecasts outcome across cancer types.

(Cancer Cell 44, 567–585.e1–e12; March 9, 2026)

(Cancer Cell 39, 529–547.e1–e7; April 12, 2021)

Across birth cohorts, in a Nature Medicine study, Tian et al. identify larger biological age gaps associated with early-onset lung, colorectal, and uterine cancers across birth cohorts. These findings position biological age as an integrative marker of physiological dysregulation. Future work combining aging clocks and mutational signatures could distinguish tumor-promoting states from tumor-initiating exposures.

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.

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.

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.

In this issue of Cancer Cell, Li et al. report a first-in-human phase 1 study of SYS6010, an epidermal growth factor receptor (EGFR)-targeting antibody-drug conjugate, in advanced solid tumors. The study highlights how EGFR-directed therapy moves beyond kinase inhibition toward antigen-guided cytotoxic delivery in non-small cell lung cancer.

Li et al. report results from a first-in-human study showing that SYS6010, an EGFR-targeted antibody-drug conjugate, demonstrates encouraging antitumor activity with a tolerable safety profile in pretreated advanced NSCLC, providing evidence that warrants further clinical development.

(Cancer Cell 41, 1118–1133.e1–e12; June 12, 2023)

In this issue of Cancer Cell, Kehl et al. construct a single-cell atlas of bone marrow T cells from patients with bone marrow-resident malignancies, identifying tumor-reactive populations existing in a state of latent competence. A 15-gene signature identifies this subset, which is expanded by immunotherapies and predicts clinical responses.

Kehl et al. characterize tumor-reactive T cells in the bone marrow of patients with multiple myeloma and AML. These cells adopt an effector state distinct from exhausted solid tumor TILs. The TFiT classifier stratifies immunotherapy, but not chemotherapy, response, identifying a latent, therapeutically engageable anti-tumor compartment.

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.

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.

In this issue of Cancer Cell, Luo et al. report an ensemble approach that integrates five pretrained pathology foundation models into a slide-level representation to exploit their complementary information, yielding improvements in tumor subtyping, biomarker, and therapy-response prediction. This shows the potential of ensemble and multimodal approaches in computational pathology.

Luo et al. develop ELF, a framework that ensembles five pathology foundation models to generate unified representations from whole-slide images. Trained on nearly 54,000 slides across 20 anatomical sites, ELF outperforms individual foundation models in disease classification, biomarker detection, and prediction of response to chemotherapy, targeted therapy, and immunotherapy.

Chen et al. present UniCure, a multi-modal foundation model that predicts drug-induced transcriptomic responses across diverse cellular contexts. By bridging cancer cell line data with patient-derived models, UniCure enables personalized drug prioritization and patient stratification, with its predicted therapeutic rankings correlating strongly with clinical survival outcomes in real-world cohorts.

(Cancer Cell 41, 1170–1185.e1–e12; June 12, 2023)

Lin et al. assemble a longitudinal pan-cancer single-cell atlas that tracks how the tumor immune microenvironment remodels during checkpoint inhibitor therapy. They show that the direction of remodeling, rather than the pre-treatment state, predicts response and translate these dynamics into a baseline gene signature that forecasts outcome across cancer types.

Manca et al. analyze >7,000 colorectal cancers, integrating next-generation sequencing and clinical data. They define tumor genomics, clonality and dosage of mutations, and metastatic tropisms and their effects on patient outcomes. Incorporating metastatic sites, primary tumor location, and genomics, they develop an organ-specific risk model for metastasis.

In this issue of Cancer Cell, Manca et al. investigate the genomic evolution and metastatic tropism of over 7,000 colorectal cancers. Integrating primary tumor location, genomic alterations, and clinical variables, they reveal how distinct patterns of tumor evolution shape metastatic competence and impact organ tropism, offering a framework to refine surveillance.

Biomarkers for immune checkpoint inhibitors have largely treated the tumor immune microenvironment as a fixed property. In this issue of Cancer Cell, Lin et al. assemble a longitudinal pan-cancer single-cell atlas and show that the direction of immune-state remodeling during therapy is more informative than baseline composition.

(Cancer Cell 44, 567–585.e1–e12; March 9, 2026)

(Cancer Cell 39, 529–547.e1–e7; April 12, 2021)

Hyeon et al. integrate protein structures with population-scale cancer genomics data to characterize significantly mutated regions in 173 cancer-relevant genes. These regions align with functional domains, three-dimensional structural constraints, and gene-specific biology, providing a framework for classifying mutation patterns in cancer genes and prioritizing sparsely annotated variants for clinical interpretation.

In Cell Press Blue, Carvalho et al. identify spatially organized tumor-macrophage niches, EMT-like CD44high cancer cells paired with SPP1/PARP14high macrophages, that drive chemoresistance in bladder cancer. PARP14 inhibition can flip this protective niche into an inflammatory, cisplatin-sensitizing state.

Across birth cohorts, in a Nature Medicine study, Tian et al. identify larger biological age gaps associated with early-onset lung, colorectal, and uterine cancers across birth cohorts. These findings position biological age as an integrative marker of physiological dysregulation. Future work combining aging clocks and mutational signatures could distinguish tumor-promoting states from tumor-initiating exposures.

Hu et al. integrate spatial multi-omics to identify stem-like lymphoid niches (SLNs) organized by CD70+ ILC2s and Tpex cells that predict PD-1/PD-L1 immunotherapy responses in hepatocellular carcinoma (HCC). They reveal that Bacillus cereus-PI-PLC increases SLN abundance and synergizes with PD-L1 blockade, highlighting microbiota-driven enhancement of cancer immunotherapy through SLNs therapeutically in HCC.