Patients with biological borderline resectable pancreatic cancer and CA19-9 levels ≥500 u/ml show worse outcomes and need tailored surgical approaches.

• Cancer-specific survival is significantly lower in patients with CA19-9 ≥500 u/ml compared to those with levels <37 u/ml (p = 0.03).
• Higher CA19-9 is linked to increased genomic mutations, with tumors showing ≥3 driver gene alterations rising along CA19-9 strata (ptrend = 0.01).
• The presence of tertiary lymphoid structures and CD8+ T-cell density decreases as CA19-9 increases, indicating an immunosuppressive environment.

Recognizing CA19-9 ≥500 u/ml may guide more aggressive management strategies for these high-risk patients.