Immune checkpoints play important roles in immune regulation, and blocking immune checkpoints on the cell membrane is a promising strategy in the treatment of cancer. Based on this, monoclonal antibodies are having much rapid development, such as those against CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein 1).But the cost of preparation of monoclonal antibodies is too high and the therapeutic effect is still under restrictions. Recently, a series of soluble immune checkpoints have been found such as sCTLA-4 (soluble CTLA-4) and sPD-1 (soluble PD-1). They are functional parts of membrane immune checkpoints produced in different ways and can be secreted by immune cells. Moreover, these soluble checkpoints can diffuse in the serum. Much evidence has demonstrated that these soluble checkpoints are involved in positive or negative immune regulation and that changes in their plasma levels affect the development, prognosis and treatment of cancer. Since they are endogenous molecules, they will not induce immunological rejection in human beings, which might make up for the deficiencies of monoclonal antibodies and enhance the utility value of these molecules. Therefore, there is an increasing need for investigating novel soluble checkpoints and their functions, and it is promising to develop relevant therapies in the future. In this review, we describe the production mechanisms and functions of various soluble immune checkpoint receptors and ligands and discuss their biological significance in regard to biomarkers, potential candidate drugs, therapeutic targets, and other topics.

Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.

The therapeutic role of ivabradine in acute myocardial infarction (AMI) remains clinically debated. This study used real-world data to evaluate the rehospitalization risk associated with ivabradine treatment for heart rate control. Among 408 patients with AMI, 76 (18.6%) received ivabradine. Kaplan-Meier analysis, log-rank test, Cox proportional hazards models, and propensity score matching (PSM) were used to assess the rehospitalization risk. Additionally, an interaction test evaluated ivabradine’s impact on the rehospitalization risk across relevant risk factors. Multiple imputation was employed to handle missing data. Multivariable Cox regression analysis revealed that ivabradine therapy was associated with a reduced risk of all-cause rehospitalization in patients with AMI before PSM (HR: 0.64; 95% CI: 0.44–0.91, P = 0.015), but not after (HR: 0.79; 95% CI: 0.50–1.24, P = 0.310). Subgroup analysis demonstrated a decreased rehospitalization risk following ivabradine therapy in females (HR: 0.44; 95% CI: 0.22–0.89, P = 0.023), and patients with heart rate > 70 bpm (HR: 0.59; 95% CI: 0.40–0.89, P = 0.011), Killip classification > 1 (HR: 0.62; 95% CI: 0.39–0.99, P = 0.046), anterior wall myocardial infarction (HR: 0.49; 95% CI: 0.26–0.93, P = 0.029), > 1 diseased vessel (HR: 0.59; 95% CI: 0.38–0.93, P = 0.023), and no chronic kidney disease (CKD) (HR: 0.67; 95% CI: 0.46–0.98, P = 0.040) or clopidogrel therapy (HR: 0.54; 95% CI: 0.32–0.90, P = 0.019). Target-range heart rate at first discharge was linked to a lower rehospitalization risk (HR: 0.74; 95% CI: 0.57–0.96, P = 0.025). Multivariable analysis indicated that ivabradine reduced the rehospitalization risk over a 12-month follow-up (adjusted HR: 0.80; 95% CI: 0.66–0.96, P = 0.017). In conclusion, ivabradine therapy during hospitalization was associated with a lower risk of all-cause rehospitalization in patients with AMI. However, the robustness of our findings requires further validation.

Hypertension and chronic kidney disease (CKD) are frequently comorbid, yet their shared genetic mechanisms remain incompletely understood. We performed a systematic multi-omics integration utilizing GWAS summary statistics (> 1.7 million individuals). Key analytical approaches and their primary findings were: (1) LD Score Regression identified significant genetic correlations (SBP-CKD: rg = 0.206, P = 4.1 × 10⁻¹⁰); (2) Bayesian colocalization (coloc/HyPrColoc) prioritized 114 shared causal variants (H4 > 0.8); (3) Transcriptome-wide association (TWAS) confirmed gene expression associations in kidney and vascular tissues; (4) Bidirectional Mendelian randomization established a causal effect of BP on CKD risk (IVW P = 3.4 × 10⁻¹⁰) with sensitivity analyses (Cochran Q, MR-Egger, leave-one-out); (5) Single-cell enrichment implicated renal tubular and vascular smooth muscle cells; (6) PheWAS evaluated pleiotropy and safety profiles of priority drug targets. We identified 434 shared BP-kidney genes, including 36 multi-trait genes associated with all four phenotypes (SBP, DBP, eGFR, CKD). The top prioritized genes (FGF5, CPS1, UMOD, SHROOM3) were supported by convergent evidence from MAGMA, TWAS, and colocalization (HyPrColoc PP = 1.00 for FGF5 and CPS1). Forward MR confirmed a causal effect of elevated SBP on CKD risk (IVW β = 0.035 per mmHg, P = 3.4 × 10⁻¹⁰), while reverse MR showed no robust evidence for reverse causation after accounting for pleiotropy (Egger intercept P = 0.001). Cell-type enrichment implicated renal tubular cells (proximal, distal, collecting duct) and vascular smooth muscle cells. Transcription factor enrichment identified HNF1A, HNF4A, and MEF2C as computationally enriched candidates. Cross-ancestry validation in East Asian populations (N ≈ 145,000) showed directionally consistent effects, although with reduced statistical power. PheWAS revealed potential pleiotropic effects for FGF5 and UMOD, informing drug safety considerations. This study constructs a genetic atlas of the “renal-vascular” axis linking systemic pressure to local renal injury, prioritizing molecular targets for precision therapeutic strategies in cardiorenal medicine.