STAT5A (Signal Transducer And Activator Of Transcription 5A)

Our findings identify SMAD7 as a key enhancer of NK-cell antitumor activity through canonical inhibition of TGF-β signaling and non-canonical activation of STAT5A transcription. Modulating SMAD7 offers a promising approach to improve NK cell-based immunotherapy.

STAT3/STAT5 mutations are early, dominant, and potentially pathogenic events in plasma cell myeloma. Their association with adverse clinical features and inferior survival supports their routine assessment and potential therapeutic targeting.

In vivo, FLC-8 inhibited MV4-11 xenograft growth (TGI: 136-178% at 10-50 mg/kg) without overt toxicity. These findings identify Cys807 as a covalent binding hotspot in FLT3 and establish FLC-8 as a promising scaffold for next-generation FLT3 inhibitor development.

Using a C57BL/6 intradermal T-cell lymphoma model, we evaluated IQDMA efficacy against conventional psoralen + UV-A (PUVA) phototherapy...Kinase-substrate network analysis revealed PAK1 substrates were 4.9-fold enriched among downregulated proteins (OR = 4.91, P = 0.011), validating the PAK-STAT axis as IQDMA's primary mechanism. These findings establish a CDC42-PAK-STAT nuclear transport axis wherein IQDMA simultaneously inhibits PAK2 kinase activity and depletes its CDC42 scaffold, creating cytoplasmic pY-STAT5 retention that uncouples phosphorylation from transcriptional execution-a dual mechanism distinct from selective JAK inhibitors that warrants clinical evaluation.

It also inhibited the expression levels of p-STAT5, p-STAT3 and p-smad2/3 in BRCA cells. We identified four hub genes closely related to the prognosis of BRCA, and a risk model constructed by these four genes may be useful for risk stratification and prognosis evaluation in BRCA patients.

In contrast, venetoclax combinations preferentially affected CD34hi cells, underscoring distinct subpopulation vulnerabilities. These findings may point to a biologically relevant mechanism underlying midostaurin resistance.

Consequently, BCR::ABL1-induced genes are hypersensitive to enhancer inhibition, and Ph+B-ALL cells are hypersensitive to enhancer-targeting drugs. Enhancer-targeting further improves the efficacy of BCR::ABL1 kinase inhibitors used for Ph+B-ALL therapy, especially in cells from IKZF1PLUS patients that most frequently relapse from current treatment, suggesting enhancer-targeting as a potential promising addition to current therapy.

Coexpression of caSTAT3 and caSTAT5 markedly enhanced the long-term proliferative capacity of CAR T cells, even in the absence of antigen stimulation or cytokine supplementation. These findings elucidate the distinct impacts of STAT3 and STAT5 activation on CAR T cell behavior and suggest that selective activation of STAT3 at optimal levels may improve CAR T cell efficacy while minimizing off-tumor toxicities.

Remarkably, Gclc deficiency impairs NK cell-mediated protection against tumor lung metastases. Our findings highlight an essential role of GSH in maintaining NK cell functionality.

Mechanistically, PD-1/IL-2 bsAb-driven STAT5 activation transcriptionally upregulates CD47 on CD8+ T cells, which shields them from macrophage-mediated phagocytosis and enhances T cell survival in the tumor microenvironment. These findings delineate a role for the IL-2-STAT5-CD47 axis in immune evasion and suggest reactivating this pathway with PD-1/IL-2 bsAb may represent a therapeutic strategy to overcome resistance in this subtype.

All four components (anti-NKp46, Fc, IL15v, anti-tumor-associated antigen) of IL15v-NKCE are essential for maximal activity, and IL15v-NKCE is more potent than the conventional NKCE when combined with anti-PD-1 in preclinical models. By integrating IL15v into our anti-NKp46 based NKCEs, IL15v-NKCE has exhibited enhanced anti-tumor efficacy while maintaining an acceptable safety profile, thereby positioning it as a promising next-generation therapeutic modality for NK cell-based therapy.

With STAT5 overexpression, the protective effect by Dbc1-/- DC was abolished in the lupus model. Therefore, targeting the DBC1-STAT5 axis in DCs diversifies the therapeutic strategies for SLE.