Large‐Scale Quantitative Morphometry of Platelet α‐Granules via SIM Super‐Resolution Microscopy for Cancer Liquid Biopsy

Blood-based liquid biopsies hold transformative potential for non-invasive cancer management, but current approaches relying on rare circulating tumor components limit their broad clinical utility. Platelets, abundant in blood and mediating diverse cancer-associated responses, represent a compelling yet largely unexplored alternative. Using SIM super-resolution microscopy, we analyzed α-granule distributions in platelets from a multicenter cohort (n = 1,556) encompassing nine cancer types and twelve non-malignant diseases. We identified robust cancer-associated alterations, particularly a marked increase in the "Circle" pattern, which exhibits excellent multi-cancer diagnostic potential. This method, termed PAID (Platelet Alpha-granule Imaging-based Diagnostic assay), achieved 85.0% accuracy in prostate cancer within the diagnostically challenging PSA "gray zone". PAID combined with PSA improved diagnostic accuracy to 94.2%, 38.4% over PSA alone, suggesting significant synergy. In ovarian cancer, PAID combined with HE4 enhanced diagnostic accuracy from 73.8% to 88.3%. Furthermore, PAID outperformed CA125 in sensitivity (90.3% vs 60.0%) for detecting ovarian cancer recurrence. We also observed that tumor cells may utilize both tumor-derived exosomes and proteins to remodel platelet α-granule distributions, suggesting the increased "Circle" pattern arises from synergistic rather than singular triggers. The non-invasive, highly accurate PAID shows great promise in advancing liquid biopsy for cancer management.