Lee et al. show that neutrophil extracellular traps (NETs) establish the pre-metastatic niche in the omentum by recruiting innate-like B cells and eliciting IL-10 production in these cells through ina...

Although immunity is an important component of cancer therapy responses, suppressive immune feedback restricting anti-tumor activity has not been extensively examined. In this issue of Cancer Cell, La...

Obradovic et al. infer and functionally validate a set of master regulator (MR) proteins specifically active in tumor-infiltrating regulatory T cells (TI-Tregs), including TRPS1. Inhibition of TRPS1 i...

Understanding αPD-1-mediated immunosuppression is necessary to improve immunotherapy. Geels et al. reveal that tumor-Treg accrual after αPD-1 blockade does not depend on enhanced TCR signaling but on ...

Cancer Cell provides a high-profile forum to promote major translational and clinical advances in cancer research and oncology.

Tay et al. discuss the potential of targeting TI-Tregs as an effective cancer therapy strategy. They review the effect of current cancer immunotherapies on TI-Tregs and the approaches that exploit dif...

The analysis of cell-free DNA (cfDNA) fragmentation patterns, known as “fragmentomics,” has opened new opportunities in noninvasive cancer diagnostics. In this Review, Tsui et al. explore the exciting frontiers of cfDNA fragmentomics, discuss critical unanswered questions, and highlight future directions to unlock the promise of fragmentomics-based liquid biopsies in cancer care.

Cheung et al. describe efficient T cell control of nascent neoantigen+ and nearby neoantigen-negative sarcoma cells, underlying a ∼50% reduction in tumor penetrance. This otherwise imperceptible immunoediting process is revealed by time-resolved profiling of autochthonously arising, muscle-derived sarcoma cells expressing fluorescent reporter-embedded model T cell antigens within the native tissue environment.

In a phase 1b randomized clinical trial, Wang et al. demonstrate the additional benefit of dual immune checkpoint inhibition as neoadjuvant treatment for locally advanced MSI-H/dMMR colon cancer. Compared with sintilimab monotherapy, IBI310 (anti-CLTA-4) plus sintilimab significantly improved pathological complete response rate, without new safety signals.

Upfront resection is the standard treatment for localized dMMR/MSI-high colon cancer. In this issue of Cancer Cell, Wang et al. showed that dual anti-CTLA-4/PD-1 IBI310/sintilimab for 6 weeks improved pathological complete response over sintilimab in patients with cT4/N+ tumors. This combination represents a referral regimen for neoadjuvant or organ-preserving strategies.

(Cancer Cell 16, 295–308; October 6, 2009)

Ren et al. demonstrate pseudo-synaptic connections between sensory neurons and pancreatic ductal adenocarcinoma (PDAC) cells. These pseudo-synapses exhibit enrichment of NMDA receptor subunit GRIN2D/GluN2D, enhancing PDAC responsiveness to neuron-derived glutamate and promoting tumor growth. Disrupting glutamate-GRIN2D signaling at pseudo-synapses improves survival in PDAC, highlighting the therapeutic potential of targeting cancer-neuron-pseudo-synapses.

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.

Chen et al. identify two distinct antigen-presenting cancer-associated fibroblast (apCAF) populations across multiple cancer types. Mesothelial-related apCAFs locate near cancer cells while fibrocyte-related apCAFs associate with lymphocyte-enriched niches. Both populations highly express SPP1, which facilitates tumor growth, metastasis, desmoplasia, and therapeutic resistance.

Migliozzi et al. use single-cell resolution spatial transcriptomics of 16 glioblastoma and 2.8 million cells to study tumor architecture. They discover that cell state coherence is maximal in cells organized within homotypic clusters with defined relationships with non-malignant cells. Dispersed cells exhibit greater plasticity, acquiring alternative phenotypes in the microenvironment and being associated with worse prognosis.

Taghbalout et al. apply collections of advanced multi-omics analyses to substantiate ecDNA’s mobile enhancer model in diverse types of cancer models, reveal the MED1-ecDNA condensates and establish their causal links to the modulation of oncogenic expression and cell proliferation. This study offers a chromatin-based mechanism of ecDNA function in cancer.

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.

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.

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.

Chen et al. demonstrate that DNASE1L3+ dendritic cells degrade neutrophil extracellular traps, thereby facilitating CD8+ T cell infiltration, effector function, and cytotoxic hub formation within the tumor microenvironment. DNASE1L3 loss compromises checkpoint blockade efficacy, whereas its restoration reinvigorates CD8+ T cell responses, offering a potential strategy to improve cancer immunotherapy.

Satpathy et al. conducted a proteogenomic analysis of 406 lung adenocarcinoma tumors across diverse demographics revealing oncogenic mechanisms, the prognostic role of chromosomal instability, immune signaling patterns, sex-specific carcinogen effects, and early-stage tumors with “late-like” traits. These biomarkers and subtype-specific therapeutic atlas advance precision strategies for this lethal disease.

Treatment resistance limits long-term effectiveness in cancer therapy. Conventional biomarkers typically rely on static gene expression levels. In this issue of Cancer Cell, Jassim et al. report a new approach, RECODR, which captures how gene relationships shift over time, uncovering hidden drivers of resistance and suggesting effective combination treatments.

In this issue of Cancer Cell, Chen et al. identify DNASE1L3-expressing dendritic cells (DCs) as enhancers of anti-tumor immunity. By degrading neutrophil extracellular traps, these DCs promote CD8⁺ T cell infiltration into tumors and enhance checkpoint blockade efficacy, extending DNASE1L3’s known immune regulatory role to physical remodeling of the tumor microenvironment.