Checkpoint blockade immunotherapy has emerged as a transformative approach in cancer treatment by activating tumor-infiltrating T cells. However, the efficacy of PD-L1 blockade is restricted in "cold" tumors, which are characterized by low immunogenicity, presenting a challenge to immunotherapy. This study introduces an innovative strategy, utilizing cathepsin-cleavable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-assisted combined photodynamic therapy (PDT) and PD-L1 degradation for the first time, effectively treating T cell-deficient tumors. The degradable main-chain polymer, conjugated with photosensitizer porphyrin, facilitates the accumulation of reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and promoting cytotoxic T lymphocytes (CTLs) infiltration into tumors. Multivalent peptide antagonists of PD-L1 promote PD-L1 degradation in lysosomes through receptor crosslinking, overcoming the adaptive cycling of PD-L1 to the tumor cell surface. These findings demonstrate that polymer-assisted PDT and PD-L1 crosslinking degradation represent a potential novel strategy for anti-tumor immunotherapy, providing valuable tools for expanding immunotherapy applications in immunosuppressive cancers.

Objective To investigate the influence of serum cystatin C (Cys-C) and hypersensitivity C-reactive protein (hs-CRP) levels on the 3-year survival of patients undergoing maintenance hemodialysis (MHD). Methods A total of 358 patients with chronic renal failure who underwent MHD at the Second Affiliated Hospital of Nantong University from April 2011 to October 2020 were selected as study subjects. General clinical data, pre-dialysis laboratory test indicators, and echocardiographic indicators 3 months after dialysis were recorded. The survival status of patients after 3 years of dialysis was followed up, and the general clinical data, pre-dialysis laboratory test indicators, and echocardiographic indicators 3 months after dialysis were compared between surviving and deceased patients. Univariate and multivariate Cox regression analyses were performed to screen influencing factors of 3-year survival in MHD patients. Results At the 3-year follow-up, of the 302 MHD patients' 203 survived, and 99 died. Statistically significant differences were observed in age, primary disease, diabetes status, congestive heart failure, statin use, antiplatelet drug use, diuretic use, dialysis mode, estimated glomerular filtration rate (eGFR) and gamma-glutamyl transferase (GGT), alkaline phosphatase (AKP), total bilirubin (TBIL), β₂-microglobulin (β₂-MG), creatinine (Cr), low-density lipoprotein cholesterol (LDL-C), hypersensitive C-reactive protein (hs-CRP), and serum phosphorus (P) levels between surviving patients and deaths(P < 0.05 or P < 0.01). Univariate Cox regression results showed that age of MHD patients, primary disease (diabetic nephropathy, hypertensive nephropathy, polycystic kidney disease, others), comorbidities(diabetes, congestive heart failure, other cardiovascular diseases), drug use (statins, antiplatelet drugs), dialysis method (hemodialysis, hemodialysis + perfusion), laboratory test indicators [GGT, AKP, TBIL, total bile acid (TBA), albumin (ALB), Cr, Cys-C, eGFR, apolipoprotein A (APO-A), hs-CRP]were all influential factors of 3-year survival rate of MHD patients. Multivariate Cox regression analysis revealed that age, primary disease, other cardiovascular diseases, dialysis mode, AKP, ALB, TBIL, Cys-C, and hs-CRP were significant influencing factors for the survival of patients with chronic renal failure (P < 0.05). Conclusion Serum Cys-C and hs-CRP levels before MHD in patients with chronic renal failure may be associated with their 3-year survival after dialysis treatment. High serum Cys-C may reduce the risk of poor clinical prognosis, while high serum hs-CRP may increase the risk of poor clinical prognosis.

Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells. The all-hydrocarbon peptide stapling technique has already widely adopted with great success, yielding numerous potent peptide-based molecules. Based on our prior efforts, we conceived and prepared a double-stapled peptide in this study, termed FRNC-1, which effectively attenuated the bone resorption capacity of mature osteoclasts in vitro through specific inhibition of phosphorylated GSK-3β. The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form. Additionally, FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized (OVX) mice after intravenous injection and importantly, after oral (intragastric) administration. The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis (PMOP).