Background and Objectives: Connexin 43 (Cx43) is involved in the transfer of small signaling molecules between neighboring cells, thereby exerting a major influence on the initiation and progression of tumorigenesis. However, there is a lack of systematic research on Cx43 expression and its predictive role in clinical diagnosis and prognosis in pan-cancer. Materials and Methods: Several biological databases were used to evaluate the expression levels of GJA1 (encoding Cx43) and its diagnostic and prognostic significance in pan-cancer. We targeted kidney renal clear cell carcinoma (KIRC) and investigated the relationship between GJA1 expression and different clinical features of KIRC patients. Then, we performed cell-based experiments to partially confirm our results and predicted several proteins that were functionally related to Cx43. Results: The expression of GJA1 has a high level of accuracy in predicting KIRC. High GJA1 expression was remarkably correlated with a favorable prognosis, and this expression was reduced in groups with poor clinical features in KIRC. Cell experiments confirmed the inhibitory effects of increased GJA1 expression on the migratory capacity of human renal cancer (RCC) cell lines, and protein–protein interaction (PPI) analysis predicted that CDH1 and CTNNB1 were closely related to Cx43. Conclusions: GJA1 could be a promising independent favorable prognostic factor for KIRC, and upregulation of GJA1 expression could inhibit the migratory capacity of renal cancer cells.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARPi may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restored NK cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlated with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells bound to ANXA6 and activated the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocked FPR1/AKT signaling and diminished the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolonged survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.

Background/Objectives: Immune checkpoint blockade targeting the PD-1/PD-L1 axis is a standard treatment for urothelial carcinoma (UC), but 20–30% of patients develop resistance. The underlying mechanisms, particularly regarding tumor microenvironment metabolic reprogramming, remain unclear. Methods: We performed single-cell RNA sequencing on pre-treatment tumors from eight pembrolizumab-treated UC patients (three responders, five non-responders). Bioinformatic analyses included cell clustering, pathway enrichment, and cell–cell communication, validated using public datasets. Functional experiments involved SGPL1 knockdown in MB49 cells and a syngeneic PD-1-resistant murine model (MB49-R5). Results: Responders exhibited a higher proportion of infiltrating T-cells. Unexpectedly, CD4⁺ subsets, rather than CD8⁺ cells, were numerically enriched in responders. However, all T-cell subsets in responders demonstrated enhanced oxidative phosphorylation-dominant metabolic activity. Enhanced macrophage–T-cell crosstalk was observed, with macrophages exhibiting M1-like polarization driven by CD4⁺ T-cell-derived IFN-γ and CD40L signaling. In contrast, non-responders displayed dominant tumor-derived MIF–CD74 signaling and M2 polarization. Integration of public datasets identified SGPL1 as a key metabolic regulator associated with poor prognosis and reduced immune activation. Functional experiments demonstrated that SGPL1 knockdown inhibited tumor proliferation and restored anti-PD-1 sensitivity, accompanied by increased T-cell infiltration. Conclusions: T-cell metabolic activation drives anti-PD-1 responses in UC, and CD4⁺ T-cell-mediated M1 polarization and tumor-intrinsic SGPL1 crucially shape therapeutic outcomes, highlighting SGPL1 as a candidate metabolic target to overcome PD-1 resistance.