Wei Wang

Introduction: Accelerated biological ageing is associated with age-related diseases, but sex differences in its association with cardiovascular disease (CVD) and premature mortality remain largely unknown. We aimed to assess the associations between biological age (BA) acceleration and CVD, premature mortality, and examine potential sex differences. Methods: This population-based prospective cohort study included participants aged 39 to 71 years from UK Biobank study, recruited between 2006 and 2010, and followed up until Dec 20, 2022. BA, derived from clinical biomarkers, was calculated using the Klemera-Doubal method (KDM-BA) and PhenoAge algorithms. BA acceleration was defined as the residual from regressing BA based on chronological age. Incident CVD and premature mortality (defined as death before age 70) were identified using ICD-9 and ICD-10 codes. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) across BA acceleration quartiles. Results: Among 122,133 participants who were free of CVD at baseline (mean [SD] age, 56.0 [8.1] years; 65,442 [53.6%] women), 24,281 incident CVD cases and 3,614 premature deaths were reported. Restricted cubic splines showed progressively increasing risks of incident CVD and premature mortality associated with higher BA acceleration. Compared with the lowest quartile of KDM-BA acceleration, the largest adjusted HRs for incident CVD and premature mortality were 1.32 (95% CI 1.27–1.37) and 1.10 (95% CI 1.05–1.21) for quartile 4, respectively. For PhenoAge acceleration, the corresponding HRs were 1.23 (95% CI 1.19–1.28) and 1.21 (95% CI 1.10–1.33), respectively. These associations were more pronounced among male participants ( P -interaction<0.05). Discussion: In this cohort study, higher BA acceleration was associated with increased risks of incident CVD and premature mortality, with more pronounced association observed in males. These findings suggest the need to exploring BA acceleration as a modifiable risk factor to optimize risk assessment, and to implement sex-specific strategies to improve health outcome.

Background: Radiotherapy (RT) and immune checkpoint inhibitors (ICIs) have each transformed the treatment of malignant solid tumors (STs). Beyond direct tumor killing, RT remodels the tumor microenvironment (TME), promotes antigen release, and enhances immune activation. ICIs targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) restore antitumor immunity by reversing T cell exhaustion. Increasing evidence indicates that RT can synergize with ICIs through mechanisms such as the abscopal effect, immunogenic cell death (ICD), and activation of the cyclic guanosine monophosphate–adenosine monophosphate (cGMP–AMP) synthase–stimulator of interferon genes (cGAS–STING) pathway. Methods: This review summarizes current radiobiological, immunological, and clinical evidence regarding the synergistic effects of RT and ICIs in malignant STs, with a focus on underlying mechanisms, recent clinical advances, and translational challenges. Results: RT can enhance tumor immunogenicity, promote immune priming, and reshape the TME to improve the efficacy of ICIs. Synergy between RT and ICIs is associated with ICD induction, cGAS‒STING activation, enhanced systemic antitumor immunity, and modulation of immune cell infiltration and checkpoint signaling. Clinical studies across multiple STs have shown encouraging efficacy and manageable safety, although outcomes vary according to tumor type, disease stage, radiation schedule, and patient selection. Conclusions: RT combined with ICIs is a promising therapeutic strategy for malignant STs. Further optimization of treatment regimens and biomarker-guided patient selection will be essential to maximize clinical benefit and enable more precise combination therapies.

Background: Immune tolerance in epithelial ovarian cancer (EOC) enables cancer cells to evade immune surveillance. Myeloid-derived suppressor cells (MDSCs), as crucial immunosuppressive regulators, shape the tumor microenvironment and contribute to resistance against immunotherapy. However, the regulatory mechanisms of MDSCs in ovarian cancer remain poorly understood. Methods: We examined the presence and distribution of MDSCs in peripheral blood and tumor tissues from EOC patients. Transcriptomic analysis was performed on ovarian cancer cells co-cultured with MDSCs. The role of Serum Amyloid A1 (SAA1) was investigated through in vitro functional assays, co-culture experiments, and in vivo mouse models. Results: MDSCs were enriched in both peripheral blood and tumor tissues of EOC patients. SAA1 was significantly upregulated in ovarian cancer cells after interaction with MDSCs and confirmed in tumor samples and cell lines. Functionally, SAA1 promoted cancer cell proliferation, migration, and invasion. It also recruited MDSCs via TLR2/4, induced the differentiation of granulocyte-monocyte progenitors (GMPs), and stimulated IL-1β secretion, which in turn enhanced SAA1 expression, forming a positive feedback loop. In vivo, SAA1 promoted tumor progression and ascites formation. Clinically, high levels of SAA1, IL-1β, and CD33⁺ MDSCs correlated with poor survival. Conclusion: This study uncovers a novel SAA1–IL-1β feedback loop that promotes immunosuppression and progression in ovarian cancer. These findings provide insight into tumor–immune interactions and suggest a potential biomarker and therapeutic target for EOC.

CKLF (chemokine-like factor)-like MARVEL transmembrane domain-containing family member 4 (CMTM4), belonging to the CMTM family of transmembrane domain proteins, plays a significant role in the initiation, progression, and metastasis of cancer. Nevertheless, its involvement in tumor immunity remains elusive. In the present investigation, we observed an upregulation of CMTM4 expression in patients with cervical cancer (CC), which also serves as a prognostic indicator for patients with CC. In vitro experiments and therapeutic models have demonstrated that CMTM4 upregulates the expansion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment via the CCL2 (C–C motif chemokine ligand 2)/CCR2 (C–C motif chemokine ligand 2) and IL-6 (interleukin-6)/GP130 (glycoprotein 130) axes. This process exerts immunosuppressive effects and promotes the occurrence and progression of CC. Mechanistically, CMTM4 interacts and stabilizes PHB2 (prohibitin 2) through post-translational modification, which further induces activation of the STING (stimulator of interferon genes)/TBK1 (TANK-binding kinase 1)/STAT6 (signal transducer and activator of transcription 6) pathway, facilitating the nuclear translocation of STAT6 which binds to the CCL2/IL-6 promoter, leading to the upregulation of CCL2/IL-6 transcription expression. Importantly, targeting CMTM4 with CMTM4-small interfering RNA enhanced the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) therapy. Our study identifies CMTM4 as a crucial determinant guiding the homing of MDSCs to CC, thereby contributing to MDSCs-mediated immune suppression and tumor progression. The combination of CMTM4 inhibition and anti-PD-1 treatment shows promising antitumor efficacy against CC. These findings offer novel insights into the tumor microenvironment and have the potential to inform the development of innovative immunotherapy approaches for CC.