Vagus nerve-derived acetylcholine regulates cross-talk between gastric cancer cells and innate lymphoid cells to upregulate PD-L1 and promote immunosuppression, revealing potential therapeutic and diagnostic strategies for gastric cancer patients.

Development of a single-cell RNA-sequencing and spatial transcriptomics cellular reference of localized prostate cancer enables identification of a spectrum of malignant epithelial phenotypes and discovery of a perineural class of fibroblast.

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies with near-universal KRAS mutation. Although KRASG12D and KRASG12V are predominant, KRASG12R is also prevalent in PDAC yet rare in other KRAS-driven cancers such as lung and colorectal adenocarcinoma, suggesting pancreas-specific selective pressures. Unlike other KRAS mutants, KRASG12R fails to productively engage key nodes that amplify oncogenic output including wild-type (WT) RAS and PI3K signaling. Furthermore, KRASG12R-mutant PDAC has been shown to be more sensitive to MAPK/ERK inhibition compared with other KRAS-mutant tumors. Three complementary studies now clarify how KRASG12R promotes PDAC growth and why this genotype may carry distinct therapeutic vulnerabilities. First, Burge and colleagues identify KRASG12R-independent PI3K maintenance driven by PTEN oxidation and broad PI3K isoform utilization, with nutrient limitation further enhancing PTEN oxidation. Second, in a separate study, Burge and colleagues develop KRASG12R mouse models and show that KRASG12R tumors exhibit reduced ERK/MAPK transcription, collagen deposition, and metastasis. Third, Kamgar and colleagues demonstrate an impaired cross-talk of KRASG12R with WT RAS and stoichiometric dependencies that help explain heightened MEK inhibitor sensitivity, supported by clinical trials combining MEK and autophagy inhibition. Together, these articles reposition KRASG12R PDAC as a biologically constrained yet therapeutically exploitable subtype. See related article by Burge et al., p. 1854 See related article by Burge et al., p. 1868 See related article by Kamgar et al., p. 2042.

Overabundance of opportunistic pathogens elevates SMOX activity via proinflammatory cytokines to accelerate breast cancer progression, which can be targeted with pharmacological inhibitors of SMOX to significantly inhibit microbiota-associated carcinogenesis.

Modifying a single base within the TIGIT gene in NK cells switches inhibitory signaling to an activating axis that enhances antitumor immunity, supporting base editing of immune cells as an immunotherapeutic strategy.

Topological features of breast cancer histology can be quantified on a continuous scale and used to accurately predict breast cancer patient survival and response to therapy.

Concomitant targeting of cancer cells and immunosuppressive tumor-associated macrophages with RGX-019-MMAE, a MERTK-targeting antibody-drug conjugate, suppresses tumor growth through direct cancer cell killing and depletion of M2 macrophages.

The COVID-19 pandemic has highlighted the long-term impact of viral infections on health, yet the impact of SARS-CoV-2 infection on lung cancer development has remained unclear. In a recent study published in Cell, Qian, Wei and colleagues describe an increased risk for the development of lung cancer in patients who suffered from past severe COVID-19. To dissect the mechanisms underlying the epidemiologic evidence, the authors used multiple murine cancer models to demonstrate that respiratory infections, including flu and SARS-CoV-2 infections, remodel the lung tissue microenvironment, leading to an accumulation of neutrophils and immunosuppressive cytokines that promote and sustain a tumor-prone environment. Tumors from previously infected mice contained not only increased numbers of pro-tumorigenic neutrophils but also CD8+ T cells that showed more pronounced signs of immune exhaustion. SARS-CoV-2 vaccination reduced the increase in cancer growth, and blocking neutrophil infiltration combined with immune checkpoint blockade reversed the increase in lung tumor burden. This study demonstrates a long-term molecular memory, or epigenetic imprinting, induced by viral infections in both epithelial and immune cells that can accelerate oncogenesis, and highlights how vaccination protects not only against acute viral infections but also limits the long-term impact of infection on future cancer development.

The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor macrophages and myeloid cells, and exhausted T-cells are all hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to show that interleukin-6 (IL-6) neutralization reprograms the glioblastoma TIME to sensitize mouse glioblastoma allografts to ICI and radiotherapy. We find rare human glioblastomas that achieve clinical responses to ICI have lower pre-treatment IL-6 levels compared to glioblastomas that do not respond to ICI. Our data show that diverse immunostimulatory gene therapies suppress local IL-6 levels in mouse glioblastoma allografts, and that IL-6 from glioblastoma cells and the tumor microenvironment is associated with reduced survival in preclinical models and in patients. We show that IL-6 blockade with a neutralizing antibody transiently sensitizes mouse glioblastoma allografts to ICI by decreasing immunosuppressive Tregs, and by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells. To translate these findings to a combination treatment strategy that could be used for patients, we show that IL-6 blockade plus ICI more durably sensitizes mouse glioblastoma allografts to immunostimulatory ablative radiotherapy.

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages, resulting in poor clinical outcomes. Ferroptosis resistance presents a major challenge in the treatment of HNSCC, highlighting the need to elucidate the mechanisms that enable HNSCC cells to evade ferroptosis. Here, we conducted a genome-wide CRISPR-Cas9 knockout screen and identified trafficking protein particle complex subunit 4 (TRAPPC4) as a key regulator of ferroptosis resistance in HNSCC. Across a comprehensive set of experimental models, including HNSCC cell lines, patient-derived organoids, cell-derived xenografts, patient-derived xenografts, Trappc4-conditional knockout mice, and lymph node and lung metastasis models, TRAPPC4 promoted tumor progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 decreased chromatin accessibility at a distal regulatory element upstream of TRIM55, thereby limiting FOS-dependent transcription. This repression reduced TRIM55-mediated GPX4 ubiquitination and degradation, resulting in GPX4 stabilization and ferroptosis resistance. Structure-based high-throughput virtual screening identified pitavastatin calcium as a TRAPPC4-binding compound that promoted TRAPPC4 degradation. Notably, pitavastatin calcium synergized with the ferroptosis inducer RSL3 to enhance ferroptotic activity and suppress HNSCC progression. These findings delineate a TRAPPC4-FOS-TRIM55-GPX4 signaling axis that drives ferroptosis resistance and tumor progression and highlight TRAPPC4 as a promising therapeutic target for ferroptosis-based intervention in HNSCC.