GZMK (Granzyme K)

This study provides an integrative single-cell and spatial atlas of CRC, revealing structured epithelial-T cell communication and spatial architecture within the tumor microenvironment. Our findings offer novel insights into immune-epithelial crosstalk and identify signaling pathways that may serve as therapeutic targets or biomarkers for CRC precision treatment.

Our data provide a structural basis for inflammaging, where fibroblasts orchestrate the complex immune aging phenotype in non-immune tissues, increasing susceptibility to age-related diseases. Bronchus-associated lymphoid tissue (BALT) enriched for GZMK+ T cells develop with ageLung adventitial fibroblasts demonstrate increased NF-kB activation with age.Fibroblast activation of NF-kB in young animals recapitulates multiple features of normal lung immune agingDepletion of GZMK+ cells decreases lung inflammation in a mouse model of acute respiratory distress syndrome (ARDS).

Subsequent multiplex immunofluorescence imaging of more than 450 primary PDAC tumors showed that the density of antigen-presenting cell (APC):Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.

The TF-miRNA regulatory network analysis uncovered 6 transcription factors (STAT5A/B, NFKB1, EGR1, RELA, and CTCF) and 4 miRNAs(hsa-miR-204, hsa-miR-148b, hsa-miR-618, and hsa-miR-103) as critical transcriptional and post-transcriptional regulators of DEGs.Integrated analyses including Kaplan-Meier survival curves, immune infiltration profiling, and comprehensive mutational analysis demonstrated significant associations with brain metastatic progression in the studied cohort. This study provides novel biomarkers from a unique perspective for the diagnosis, prognosis, and development of molecular-targeted therapies or immunotherapies for brain metastasis in NSCLC.

Furthermore, the release of cytotoxic cargo by degranulation could be induced by stimulation of CD4+ cells in cultures of FL and DLBCL suspensions. In line, the direct cytotoxic capacity of TF K cells against lymphoma cells was demonstrated by killing assays with isolated cells, underscoring their potential as a prospective therapeutic target in lymphoma control.

These CD8+CTLs secrete different cytokines (IFN-γ and IL-10) and cytotoxic molecules (perforin and Gzms), which exert immunoregulatory actions to maintain immune homeostasis. The article concludes with a future perspective and a conclusion section, highlighting the critical need to understand CD8+CTLs' cytotoxic and immunoregulatory functions in maintaining immune homeostasis across various diseases, including those with newly identified roles for CD8+CTLs.

Our study provides the first comprehensive map of T cell clonal dynamics and differentiation in glioblastoma following dual ICIs and highlights a potential mechanism of immune activation and peripheral recruitment of TRC in glioblastoma not previously described. Our results suggest that therapeutic strategies to sustain these GZMK hi early effector and transitional effector T cells may further enhance ICI therapeutic efficacy in glioblastoma.

This study highlights the pivotal role of T cell subsets in patients with metastatic dMMR CRC who resistance to anti-PD-1 therapy, revealing that transcriptional dysregulation and impaired cell communication networks are central mechanisms underlying drug resistance. Notably, KLRB1 has been identified as a promising biomarker for immunotherapy response in CRC patients.

We identified characteristic arterial imaging changes resulting from radiation injury, accurately and dynamically assessing the effects of radiation exposure on plaque stability. Radiation exposure affected plaque stability by modulating GZMK+ CD8+ T-cell activation and GZMB function, suggesting GZMB as a mediator of radio-cardiovascular injury and a potential therapeutic target.

Here, we investigated a polymer-based chemo-immunotherapy strategy combining KT-1, a backbone-degradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin conjugate that induces immunogenic cell death (ICD), with MPPA, a multivalent HPMA copolymer-peptide antagonist of PD-L1 (PPA: (NYSKPTDRQYHF)...Importantly, MPPA did not induce autoimmune diabetes in NOD mice, in contrast to conventional anti-PD-L1 antibodies, and showed no observed immune-related adverse effects highlighting the safety. These findings support HPMA copolymer-based chemo-immunotherapy as a safer, effective alternative to traditional ICI regimens for treating immune-excluded tumors.

Treatment with rituximab depletes this population, suggesting potential therapeutic implications. Our findings establish CD20+ NK cells as a functionally distinct lymphocyte subset with enhanced effector capabilities and tissue-homing properties, providing new insights into immune regulation in inflammatory diseases.

Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapse-free survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering more potent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).