Rade et al. present a longitudinal single-cell atlas of BCMA CAR-T therapy in multiple myeloma, revealing that cilta-cel drives potent CD4⁺ cytotoxic responses and superior outcomes. Their findings identify plasmacytoid dendritic cells as unexpected BCMA-expressing targets and suggest therapeutic potential in blastic plasmacytoid dendritic cell neoplasm.

Glioblastoma features extensive gene expression heterogeneity and high lethality, yet the mechanisms underlying this heterogeneity and its link to clinical outcomes remain elusive. In this issue of Cancer Cell, Migliozzi et al. spatially profile glioblastoma specimens to uncover cellular mechanisms that govern the extent of the heterogeneity in malignant cells.

Extrachromosomal circular DNA (ecDNA), enriched with enhancers, drives oncogenic transcription and tumor progression, but the mechanisms remain elusive. In this issue of Cancer Cell, Wei et al. uncover MED1-driven ecDNA super-enhancers as regulatory hubs and show that disrupting ecDNA-containing condensates selectively impairs transcription and induces apoptosis in a cancer-type-specific manner.

Zhang et al. show that CRC cells adopt a Paneth-like state to evade dual KRAS and EGFR inhibition. They identify a SMAD1-FGFR3 axis that drives lineage plasticity and MAPK reactivation, conferring resistance. FGFR3 co-targeting blocks this transition, offering a strategy to improve the durability of KRAS-EGFR combination therapies.

Exercise holds significant potential as an adjunct therapy in cancer, extending beyond quality-of-life improvements to influencing tumor progression, treatment response, and survival. Its clinical integration remains limited by variability in models, heterogenous interventions, and the absence of predictive biomarkers. As the field progresses, identifying molecular effectors of exercise, in addition to emphasizing practical clinical translation, is essential. This commentary highlights the anti-tumor effects of exercise and evaluates how exercise can advance from supportive care to a targeted, evidence-based component of cancer treatment.

Immunotherapy as single-agent PD-1 blockade does not work for patients with microsatellite stable (MSS) colorectal cancer. In this issue of Cancer Cell, Morris et al. demonstrate that targeting the mitogen-activated protein kinase (MAPK) pathway in combination with immunotherapy can reprogram BRAF-V600E mutant MSS colorectal cancers toward immune responsiveness.

Glioblastoma alters normal brain function by hijacking neural circuits. In this issue of Cancer Cell, Yang et al. elucidate the mechanisms by which glioblastoma exploits cholinergic signaling pathways to disrupt the hierarchical organization of brain networks. These insights help redefine tumor-brain interactions and open new therapeutic avenues.

Harnessing the cytotoxic potential of natural killer (NK) cells for cancer immunotherapy has proven challenging. In this issue of Cancer Cell, Biederstädt et al. and Nikolic et al. utilize genome-wide CRISPR screening to uncover novel regulators of NK cell function, paving the way for developing next-generation NK cell therapies.

Allogeneic NK cell immunotherapy offers a promising, off-the-shelf treatment for relapsed and refractory cancers. In this review, Biederstädt et al. highlight early clinical trial findings, innovative engineering approaches, and discovery platforms that identify targets for creating multi-engineered CAR-NK cells to enhance efficacy against solid tumors and integrate into cancer immunotherapy.

We propose an emerging strategy for advanced cancer treatment based on progressive, stepwise remodeling of tumor microenvironments (TMEs). TMEs are variable but show conserved archetypes across patients and tissue origins. Deep learning over single-cell atlases collected from perturbed tumors can uncover gene and cellular networks shifting between archetypes. This allows for designing “nudge” or “state-shifting” drugs whose sequential application achieves stepwise transformation of a TME from an adverse to a more favorable state, dismantling deleterious tumor-host interactions to achieve patient remission.

Wang et al. analyze IPMNs, normal samples, pancreatic cyst fluids, and PDACs using proteomics and glycoproteomics, identify high-grade-IPMN-associated proteins in both tissues and cyst fluids, and link ECM protein alterations to disease progression. These findings offer insights into neoplastic progression in the pancreas and highlight potential biomarkers for early detection and therapy.

Chen et al. report that the ketogenic diet inhibits glioma progression by promoting microbiota-derived butyrate production through remodeling the gut microbiota in a mucin-2-dependent manner, whereby inducing a tumor-inhibitive phenotype of microglia via activating caspase-3.

Grandis et al. evaluate the activity of a cyclic oligonucleotide inhibitor of STAT3, CS3D, in immunocompetent models of mouse head and neck cancer and in a clinical trial of pet cats with oral cancer. CS3D has low toxicity and modulation of immune parameters is associated with anti-tumor activity.

Salgia et al. unravel the preferential immune sensitivity of sarcomatoid renal cell carcinoma, revealing heightened tertiary lymphoid structure expression and anti-tumor humoral immune activity. They furthermore generate a transcriptomic signature that captures the simultaneous hyper-aggressive yet immune-responsive nature of sarcomatoid RCCs irrespective of sarcomatoid feature presence.

Microsatellite stable BRAFV600E CRC is characterized by higher immune activation and clinically poor prognosis. Morris et al. demonstrate durable clinical benefit to encorafenib, cetuximab, and nivolumab in this phase 1/2 clinical trial. Extracellular vesicle and tumor RNA profiling both link specific immune activation signatures to treatment efficacy.

Tang et al. apply spatiotemporal multi-omics to define four proteomic subtypes of IDH-mutant astrocytoma. They highlight an immune/mesenchymal-enriched (IME) subtype marked by gemistocytic differentiation, immune infiltration, and poor prognosis. Their AI-powered toolbox, GUIDE, enables multi-omics-based classification and supports precision diagnostics in glioma care.

Biederstädt et al. conduct genome-wide CRISPR screens in primary human NK cells, identifying MED12, ARIH2, and CCNC as critical regulators of antitumor activity. Targeted knockout of these genes enhances CAR-NK cell cytotoxicity, cytokine release, and metabolic fitness, providing a mechanistic framework for developing next-generation NK cell therapies against treatment-resistant malignancies.

Tumor microenvironment IL-15 can regulate anti-tumor immunity. In this study, Nikolic et al. perform genome-wide CRISPR screening in natural killer cells and discover that UBE2F-dependent activation of the Cullin-5 RING E3 ligase (CRL5) complex results in IL-15R degradation and signaling inhibition. Targeting UBE2F enhances anti-tumor immunity of natural killer cells.

Glioblastoma is shaped by neural integration. Using brain-wide input mapping, Yang et al. reveal complex neuron-glioma connectivity and show that long-range cholinergic input promotes tumor growth via muscarinic receptors in a circuit-specific manner. Dual blockade of cholinergic and glutamatergic signaling yields additive anti-tumor effects, highlighting attractive therapeutic targets for glioblastoma.

Gao et al. characterize the tumor microenvironment dynamics following total neoadjuvant therapy (TNT) in locally advanced rectal cancer using a multi-omics approach. They uncover a unique interaction between IFNG+CD8+ T cells and ACKR1+ endothelial cells, suggesting a potential positive feedback loop mediated by the IFNG-IFNGR axis and enhanced antigen presentation by endothelial cells after TNT.

The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.

Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.

By single-cell and spatial transcriptomics analysis, Peng et al. reveal that alveolar progenitors are the earliest predecessor of LUAD and reside in epithelial-proinflammatory niches that are more common in premalignant stages and enriched with IL-1β-IL1R1 signaling. Targeting IL-1β and these niches in mice reduces alveolar progenitors and development of LUAD.

For resectable pancreatic cancer, upfront surgery followed by adjuvant therapy has long been the standard of care. A randomized trial by Bai et al. in Cancer Cell demonstrates that sequential neoadjuvant gemcitabine/nab-paclitaxel followed by mFOLFIRINOX significantly improved event-free survival compared with upfront surgery, supporting a shift toward a sequential neoadjuvant approach in this setting.