Dominic P. Golec, Pamela L. Schwartzberg and colleagues (National Institute of Allergy and Infectious Diseases (NIAID)) describe a PI3 Kinase-Foxo1-FasL signaling circuit that promotes amplified signaling and rewires transcriptional and epigenetic programs driving IFN-γ and altered T helper cell differentiation in CD4+ T cells from mice expressing an activating mutant of phosphoinositide 3-kinase delta.

Immunodeficiency LymphocyteBiology

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While inputs regulating CD4⁺ T helper (Th) cell differentiation are well defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th lineage identity remains incompletely resolved. PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated PI3Kδ, we found aberrant expression of proinflammatory Th1 signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kδ-IL-2-Foxo1 signaling amplification loop, fueling Foxo1 inactivation, loss of Th2 lineage restriction, and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated PI3Kδ, thereby linking two key pathways of immune dysregulation.

Kathrynne Warrick, Chandrashekhar Pasare et al. show that PD-1 blockade leads to de novo priming of self-reactive CD8 T cells resulting in immune related adverse events.

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Immune checkpoint inhibitors (ICIs) improve cancer survival but can trigger immune-related adverse events. Among these, fulminant myocarditis is an often fatal complication with limited therapies. We developed a mouse model employing cardiomyocyte-restricted antigen expression to define how ICIs drive cardiac autoimmunity. Combined cytotoxic T cell antigen-4 (αCTLA-4) and programmed death-1 (αPD-1) blockade uniquely induced robust expansion of antigen-specific CD8 T cells, myocardial inflammation, and lethal arrhythmias. PD-1 blockade alone permitted the priming and effector differentiation of naive autoreactive CD8 T cells, whereas concomitant CTLA-4 inhibition amplified cardiac pathology. Unexpectedly, myocardial injury was independent of perforin-mediated cytotoxicity but critically depended on T cell–derived TNF, which promoted myeloid recruitment, cytokine production, and arrhythmogenesis. Genetic ablation of CD8 T cell–derived tumor necrosis factor (TNF) or TNF receptor 2 (TNFR2) blockade prevented cardiotoxicity while preserving antitumor efficacy. These findings establish a TNF-TNFR2–driven inflammatory circuit downstream of autoreactive CD8 T cells as a central mechanism of ICI myocarditis and a strategy to uncouple cardiotoxicity from immunotherapy benefits.

The next-generation anti-cancer therapeutics must disrupt intracellular mechanics, efficiently eradicating cancer cells, rather than simply intoxicating them. We evaluate the mechanism of action of PCMS, a PAMAM-based supramolecule that eradicates cancer cells by reorganizing their internal mechanics rather than their genes. Once internalized, PCMS self-assembles into a perinuclear ring that severs nucleus-cytoskeleton communication. We observed PCMS’s dual-intelligent mechanisms of action: Cytoskeletal rescue, where actin-microtubule filaments move towards the PCMS ring, treating it as a surrogate plasma membrane, attempting to restore vesicular trafficking; Nuclear counter-expansion, where chromatin-lamina condensates undergo stepwise viscoelastic transitions that push the nuclear envelope outward to reestablish membrane contact. These contradictory forces amplify mechanical stress, driving super-critical strain and nuclear lysis without broad transcriptional modulations. By geometry alone, PCMS collapses the actin-microtubule-nucleus continuum and turns the cell’s adaptive machinery into its own executioner. The discovery that life and death decisions can be reprogrammed through spatial conflict establishes a paradigm of mechanical deception, inaugurating a new class of cellular adaptive feedback-targeted mechanotherapeutics that overcome resistance by exploiting the cell’s own morphogenetic logic.

Maureen A. Su find the epigenetic regulator UTX complexes with transcription factors TCF1 and STAT3 to promote pathogenicity of long-lived, stem-like progenitor T cells in models of type 1 diabetes (T1D)

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¹Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, California, USA.

²Department of Pediatrics and.

³Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Genetic off switch for cancer face_with_colon_three #cancer #cure

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Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

Prostate cancer often develops very slowly. For the vast majority, this is a disease that you live well with, without the need for treatment, but some get an aggressive variant with recurrence of cancer even after surgery. The disease behaves very differently from patient to patient. Understanding what makes the cancer aggressive is crucial for better diagnostics and treatment, says the author.

Aggressive cancer has its own gene expression: The researchers identified a pattern in the gene expression of the tumor itself in prostate tissue in patients with a high risk of recurrence and spread. This signature can become a new tool for distinguishing between patients who need intensive care and those who can manage with less intensive follow-up.

Inflammation of apparently healthy tissue: Signs of inflammation and changes in metabolic processes were also found in the normal tissue close to the cancerous tumor. These glands had high activity of neurotransmitters that attract immune cells, and an increased occurrence of a cell type that can trigger inflammatory reactions. At the same time, the levels of important substances had decreased, suggesting that the gland had lost its normal function.

“Aggressive prostate cancer appears to be associated with inflammation in the area around the cancer cells, combined with specific genetic signatures and metabolic changes in the prostate tissue. This knowledge can provide better methods for early identification of patients at high risk,” says the author. ScienceMission sciencenewshighlights.

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The research lays a foundation for the possibility that aggressive prostate cancer can probably be detected through a few drops of semen or blood in the long term.

Prostate cancer is the most common form of cancer among men in Western countries.

Here, Barbara Rivera & team report on the benign-to-malignant progression route in DICER1/DGCR8-thyroid lesions, identifying a DICER1-cancer epi-signature using multi-omic profiling:

The image depicts a thyroid lesion from a sporadic DICER1 case with immunofluorescent staining for pan-cytokeratin (green) and vimentin (red). Enclosed areas represent selected regions of interest.

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¹Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain.

²Genetics Program, Faculty of Biology, and.

³Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.