Jin He

Personalizing CA125 Levels Using Tumor Marker Variants: A Case–Control Analysis of Diagnostic Performance for Pancreatic Cancer

Abstract Background: Cancer antigen 125 (CA125) is widely recognized as a useful biomarker for the surveillance of patients with ovarian and other cancers. Prior genome-wide association studies have identified variants that influence CA125 levels. We evaluated the utility of stratifying CA125 levels by such variants and evaluated diagnostic performance in control subjects and patients with pancreatic ductal adenocarcinoma (PDAC). Methods: We measured CA125 levels in 807 control subjects and 450 patients with PDAC and genotyped 10 variants involving four genes (GAL3ST2, MSLN, D2HGDH, and MUC16). We compared CA125 levels in controls by variant and generated variant-defined CA125 cutoffs and then classified cases and controls into functional groups based on their variant profile. We used this variant classification to evaluate the diagnostic performance of CA125 in patients with PDAC. Results: Six variants associated with CA125 levels were used to group controls into one of four groups. Mean CA125 levels in the highest variant group were approximately fourfold higher than in the lowest group. African Americans were more likely to have a variant group associated with low CA125 levels. After setting diagnostic cutoffs by variant group, the diagnostic sensitivity of CA125 for PDAC was 20.2% at 98% specificity (areas under the ROC curve, 0.702), not significantly different from a uniform CA125 diagnostic cutoff (areas under the ROC curve, 0.700). Conclusions: Gene variants can be used to generate personalized CA125 reference ranges. This approach did not significantly improve CA125’s diagnostic performance for pancreatic cancer, but it merits evaluation in other diagnostic settings, such as detecting ovarian cancer. Impact: Gene variants can be used to personalize CA125 levels.

UTND Effect Mediates Macrophage Ferroptosis and Promotes Immune Microenvironment Remodeling of Ovarian Cancer

ABSTRACT Tumor‐associated macrophages (TAMs) act as a vital player in the immunosuppressive tumor microenvironment (TME) and have received widespread attention in the treatment of cancer in recent times. Nevertheless, simultaneously inducing TAM repolarization and strengthening their phagocytic ability on cancer cells is still a significant challenge. Ferroptosis has received widespread attention due to its lethal effects on tumor cells, but its role in TAMs and its impact on tumor progression have not yet been defined. Here, M2‐type tumor‐associated macrophages (M2‐TAMs) targeted nanobubbles (NBs)‐based (M2‐pep@SF‐NBs) were constructed for ultrasound‐controlled delivery of the ferroptosis agonist sorafenib (SF) to enhance macrophage‐mediated cancer immunotherapy. SF causes ferroptosis of M2 and regulates repolarization to M1 and promotes intratumoral (cytotoxic T lymphocyte) CTL infiltration, leading to activation of the TME that significantly inhibits tumor growth. Additionally, ultrasound (US)‐induced macrophage ferroptosis notably improved the effectiveness of anti‐PD‐1 (aPD‐1) therapy against tumors. M2‐pep@SF‐NBs were constructed to specifically target macrophage ferroptosis and repolarization, and combining this treatment with aPD‐1 exerted significant anti‐tumor efficacy. These findings lay the groundwork for deeper exploration of ferroptosis activation in TAMs and the regulation of their infiltration and function, aiming to enhance tumor prevention and therapeutic outcomes.