Malignant B cells rely on B cell receptor (BCR) signals for their survival and growth. Besides the Immunoglobulin M (IgM) BCR, lymphoma cells can also express non-IgM (IgG) BCRs; however, the role of IgG BCRs in malignant B cell is not well understood. Here, we report poorer disease outcomes in diffuse large B cell lymphoma (DLBCL) expressing high IgM versus those expressing IgG1. Using isogenic lymphoma cells expressing distinct BCRs, we found that IgM expressing cells strongly outcompete their IgG1 counterparts. Mechanistically, IgG1 BCR is associated with a dysfunctional mitochondrial state and reduced cell survival. We show that mitochondrial dysfunction is triggered by accentuated calcium responses downstream of IgG1 BCR. Genetic reversal of IgG1 to IgM, pharmacological dampening of calcium signaling, or treatment with interleukin-21 can correct mitochondrial defects and rescue IgG1 survival. Our findings demonstrate that distinct BCR isotypes are inherently unique and can differentially affect B cell lymphoma pathogenesis.

Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes1-5. Here we studied ICB response in a cohort of patients with ovarian clear cell carcinoma-a cancer type that poses considerable clinical challenges and lacks effective therapies6-8. We observed significantly prolonged overall survival and progression-free survival in patients with tumours with PPP2R1A mutations. Importantly, our findings were validated in additional ICB-treated patient cohorts across multiple cancer types. Translational analyses from tumour biopsies demonstrated enhanced IFNγ signalling, and the presence of tertiary lymphoid structures at the baseline, as well as enhanced immune infiltration and expansion of CD45RO+CD8+ T cells in the tumour neighbourhood after ICB treatment in PPP2R1A-mutated tumours. Parallel preclinical investigations showed that targeting PPP2R1A (by pharmacological inhibition or genetic modifications) in in vitro and in vivo models was associated with improved survival in the setting of treatment with several forms of immunotherapy, including chimeric antigen receptor (CAR)-T cell therapy and ICB. The results from these studies suggest that therapeutic targeting of PPP2R1A may represent an effective strategy to improve patient outcomes after ICB or other forms of immunotherapy, although additional mechanistic and therapeutic insights are needed.
© 2025. The Author(s).

Cellular senescence represents a permanent state of cell cycle arrest, also observed in neurodegenerative disorders. As p300 has been identified as an epigenetic driver of replicative senescence, we aimed to investigate whether in vitro p300 inhibition could rescue the stress-induced premature senescence (SIPS) phenotype. We exploited 2D and 3D (brain organoids) in vitro models of SIPS using two different stressor agents. In addition, we combined the treatment with a p300 inhibitor and validated p300 role in SIPS by analyzing different senescence markers and the transcriptome in our models. Interestingly, p300 inhibition can counteract the DNA damage and SIPS phenotype, detecting a dysregulation of gene expression and protein translation associated with the senescence program. These findings highlight both the molecular mechanisms underlying senescence and p300 as a possible pharmacological target. Thus, targeting p300 and, by extension, senescent cells could represent a promising therapeutic strategy for age-related diseases such as neurodegenerative disorders.
© 2025. The Author(s).

Resistance to immune checkpoint blockade (ICB) therapy remains a major obstacle to successful cancer treatment and represents a significant unmet clinical need. Identifying clinically actionable targets to overcome this resistance is therefore essential for developing effective combination strategies with ICB. In this study, using transcriptomic data from cancer patients treated with programmed cell death protein 1 (PD-1) therapy and established mouse preclinical PD-1 blockade-resistant models, we identify transient receptor potential vanilloid 1 (TRPV1) as a crucial mediator that enables tumor cells to resist cytotoxic T lymphocyte (CTL)-mediated killing, thereby facilitating immune escape from PD-1 therapy. Mechanically, TRPV1 enhances autophagy-dependent secretion of epidermal growth factor (EGF), which in turn activates epidermal growth factor receptor (EGFR) signaling, ultimately leading to tumor cell resistance to CTL-mediated cytotoxicity. Importantly, pharmacological inhibition of TRPV1 sensitizes resistant tumors to PD-1 blockade by restoring anti-tumor immune response. Thus, our findings highlight TRPV1 as a promising therapeutic target for overcoming resistance to PD-1 blockade and provide a strong rationale for combining TRPV1 antagonists with anti-PD-1 therapy.
© 2025. The Author(s).

Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.
© 2025. The Author(s).