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Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP / EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP / EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment. Mutations in histone acetyltransferases (HATs) CREBBP and EP300 are generally thought to lead to decreased function or absence of protein product. Here the authors describe a gain of function of several CREBBP mutations leading to baseline hyper-acetylation, increased homologous recombination and potential synergy between radiation and HAT inhibition in CREBBP/EP300 mutant tumors.

, the most mutated gene in solid cancers, has a profound impact on most hallmarks of cancer. Somatic mutations occur in high frequencies in head and neck cancers, including oral squamous cell carcinoma (OSCC). Our study aims to understand the role of gain-of-function mutation in modulating the tumor immune microenvironment (TIME) in OSCC. Short hairpin RNA knockdown of mutant in syngeneic oral tumors demonstrated changes in tumor growth between immunocompetent and immunodeficient mice. HTG EdgeSeq targeted messenger RNA sequencing was used to analyze cytokine and immune cell markers in tumors with inactivated mutant . Flow cytometry and multiplex immunofluorescence (mIF) confirmed the role of mutant in the TIME. The gene expression of patients with OSCC was analyzed by CIBERSORT and mIF was used to validate the immune landscape at the protein level. Mutant contributes to a cytokine transcriptome network that inhibits the infiltration of cytotoxic CD8 T cells and promotes intratumoral recruitment of regulatory T cells and M2 macrophages. Moreover, also regulates the spatial distribution of immunocyte populations, and their distribution between central and peripheral intratumoral locations. Interestingly, -mutated tumors are infiltrated with CD8 and CD4 T cells expressing programmed cell death protein 1, and these tumors responded to immune checkpoint inhibitor and stimulator of interferon gene 1 agonist therapy. CIBERSORT analysis of human OSCC samples revealed associations between immune cell populations and the mutation, which paralleled the findings from our syngeneic mouse tumor model. These findings demonstrate that syngeneic tumors bearing the gain-of-function mutation modulate the TIME to evade tumor immunity, leading to tumor progression and decreased survival.

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.

Nanovesicles (NVs) are emerging as innovative, theranostic tools for cargo delivery. Recently, surface engineering of NVs with membrane proteins from specific cell types has been shown to improve the biocompatibility of NVs and enable the integration of functional attributes. However, this type of biomimetic approach has not yet been explored using human neural cells for applications within the nervous system. Here, this paper optimizes and validates the scalable and reproducible production of two types of neuron‐targeting NVs, each with a distinct lipid formulation backbone suited to potential therapeutic cargo, by integrating membrane proteins that are unbiasedly sourced from human pluripotent stem‐cell‐derived neurons. The results establish that both endogenous and genetically engineered cell‐derived proteins effectively transfer to NVs without disruption of their physicochemical properties. NVs with neuron‐derived membrane proteins exhibit enhanced neuronal association and uptake compared to bare NVs. Viability of 3D neural sphere cultures is not disrupted by treatment, which verifies the utility of organoid‐based approaches as NV testing platforms. Finally, these results confirm cellular association and uptake of the biomimetic humanized NVs to neurons within rodent cranial nerves. In summary, the customizable NVs reported here enable next‐generation functionalized theranostics aimed to promote neuroregeneration. Membrane proteins are extracted from either human pluripotent stem cells or differentiated neurons and combined with lipids to synthesize biomimetic nanovesicles (NVs). Neural targeting of NVs can be evaluated both in vitro using monolayer cultures and 3D organoids and in vivo by direct injection of NVs into murine trigeminal ganglions.

Background The management of sub-totally resected sporadic vestibular schwannoma (VS) may include observation, re-resection or irradiation. Identifying the optimal choice can be difficult due to the disease’s variable progression rate. We aimed to define an immune signature and associated transcriptomic fingerprint characteristic of rapidly-progressing VS to elucidate the underpinnings of rapidly progressing VS and identify a prognostic model for determining rate of progression. Methods We used multiplex immunofluorescence to characterize the immune microenvironment in 17 patients with sporadic VS treated with subtotal surgical resection alone. Transcriptomic analysis revealed differentially-expressed genes and dysregulated pathways when comparing rapidly-progressing VS to slowly or non-progressing VS. Results Rapidly progressing VS was distinctly enriched in CD4 + , CD8 + , CD20 + , and CD68 + immune cells. RNA data indicated the upregulation of anti-viral innate immune response and T-cell senescence. K − Top Scoring Pair analysis identified 6 pairs of immunosenescence-related genes ( CD38-KDR, CD22-STAT5A, APCS-CXCR6, MADCAM1-MPL, IL6-NFATC3, and CXCL2-TLR6 ) that had high sensitivity (100%) and specificity (78%) for identifying rapid VS progression. Conclusion Rapid progression of residual vestibular schwannoma following subtotal surgical resection has an underlying immune etiology that may be virally originating; and despite an abundant adaptive immune response, T-cell immunosenescence may be associated with rapid progression of VS. These findings provide a rationale for clinical trials evaluating immunotherapy in patients with rapidly progressing VS.

The critical role of the tumor immune microenvironment (TIME) in determining response to immune checkpoint inhibitor (ICI) therapy underscores the importance of understanding cancer cell–intrinsic mechanisms driving immune-excluded (“cold”) TIMEs. One such cold tumor is oral cavity squamous cell carcinoma (OSCC), a tobacco-associated cancer with mutations in the TP53 gene which responds poorly to ICI therapy. Because altered TP53 function promotes tumor progression and plays a potential role in TIME modulation, here we developed a syngeneic OSCC models with defined Trp53 ( p53 ) mutations and characterized their TIMEs and degree of ICI responsiveness. We observed that a carcinogen-induced p53 mutation promoted a cold TIME enriched with immunosuppressive M2 macrophages highly resistant to ICI therapy. p53 -mutated cold tumors failed to respond to combination ICI treatment; however, the combination of a programmed cell death protein 1 (PD-1) inhibitor and stimulator of interferon genes (STING) agonist restored responsiveness. These syngeneic OSCC models can be used to gain insights into tumor cell–intrinsic drivers of immune resistance and to develop effective immunotherapeutic approaches for OSCC and other ICI-resistant solid tumors. Oral squamous cell carcinoma models are presented with defined Trp53 mutations associated with immune checkpoint inhibitor responsiveness, e.g. T122N amino acid change of Tp53 promotes a cold TME enriched with immunosuppressive M2 macrophages resistant to ICI therapy.

Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to immunotherapy. The interplay between β‐adrenergic signaling and p53 loss, both key regulators of immune responses, has remained largely unexplored in the setting of tumor‐immune evasion. This study demonstrates that pharmacologic stimulation of β2‐adrenergic receptors with isoprenaline significantly enhances cytotoxic T cell activity against p53‐deficient HNSCC cells via a CXCL10‐dependent paracrine mechanism. Comprehensive transcriptomic and co‐culture assays reveal that p53‐null cancer cells upregulate CXCL10, which promotes CD8+ T cell recruitment and activation. Neutralization of CXCL10 abolishes the β‐adrenergic‐induced cytotoxic T cell response, establishing this chemokine as a pivotal mediator. Using tyrosine hydroxylase knockout mouse models, we show that adrenergic innervation is essential for intra‐tumoral CXCL10 expression and the infiltration of effector CXCR3+ T cells in vivo. Notably, the CXCL10‐driven T cell response is associated with simultaneous upregulation of both activation and exhaustion markers, indicating a robust but transient effector state within the tumor microenvironment. Collectively, these findings uncover a neuro‐immune axis that reverses immune escape in p53‐deficient HNSCC and suggest novel therapeutic strategies targeting adrenergic signaling to convert immune “cold” tumors into “hot” ones more amenable to immunotherapy. β‐adrenergic stimulation enhances anti‐tumor immunity in TP53‐deficient oral squamous cell carcinoma by inducing tumor‐derived secretion of CXCL10, which attracts and activates cytotoxic CD8+ T cells. The findings demonstrate that β‐adrenergic signaling alters tumor–immune interactions via CXCL10‐mediated paracrine activation, revealing a neuro‐immune axis that overcomes immune escape in p53‐deficient tumors.

Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work.

Activation of the sympathetic nervous system releases catecholamines that can interact with β‐adrenergic receptors on tumor cells. Preclinical models have shown that the signaling processes initiated by activation of β‐adrenergic receptors increase tumorigenesis, stimulate cell proliferation, and inhibit apoptosis. Indeed, preclinical studies have also shown that β‐adrenergic blockade can decrease tumor burden. Researchers have been studying the effects of β‐adrenergic receptor blockers on tumor cells and how they may slow the progression of melanoma, basal cell carcinoma, and squamous cell carcinoma. Moreover, clinical data have shown improved prognosis in patients with skin cancer who take β‐blockers. This review discusses the mechanisms of β‐adrenergic signaling in cancer and immune cells, details preclinical models of sympathetic blockade, and considers clinical evidence of the effects of β‐adrenergic blockade in skin cancers.

Humanized Biomimetic Nanovesicles In article number 2101437, Assaf Zinger, Francesca Taraballi, Robert Krencik, and co‐workers optimize and validate the scalable production of neuron‐targeting biomimetic nanovesicles (NV) with distinct lipid backbones suited to potential therapeutic cargo by integrating membrane proteins from human pluripotent stem cell‐derived neurons. NVs with neuronderived membrane proteins exhibit enhanced neuronal association and uptake compared to bare NVs. These customizable NVs enable next‐generation functionalized theranostics for neurodegeneration.