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Siglec‐15, a novel immune checkpoint, is an emerging target for next‐generation cancer immunotherapy. However, the role of Siglec‐15 in pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. We investigated the expression of Siglec‐15 and its association with clinicopathological characteristics, programmed cell death‐ligand 1 (PD‐L1), immune cells, and DNA damage repair (DDR) molecules in a cohort of 291 patients with PDAC. Positive tumour cell expression of Siglec‐15 and PD‐L1 was observed in 18.6 and 30.3% of the samples, respectively. We also detected Siglec‐15 positivity in macrophages in 3.4% of patients. Co‐expression of Siglec‐15 with PD‐L1 was observed in 6.1% of the patients. A total of 33 PD‐L1‐negative samples (18.0%) were Siglec‐15‐positive. Siglec‐15 was observed more frequently in moderate‐to‐well‐differentiated tumours. Siglec‐15 was associated with a low density of Tregs and CD45RO T cells, high BRCA1 expression, and improved survival. Both Siglec‐15 and PD‐L1 are independent factors of patient outcomes. The prognostic significance of Siglec‐15 for survival was more discriminative in lymph node‐negative, high BRCA1 expression, or low BRCA2 expression tumours than in lymph node‐positive, low BRCA1 expression, or high BRCA2 expression tumours. In conclusion, we identified Siglec‐15 as a promising predictor for prognosis combined with different DDR molecular statuses and complex tumour‐infiltrating cells in PDAC. Targeting Siglec‐15 may be a novel therapeutic option for patients who are unresponsive to anti‐PD‐1 therapy. Future studies are needed to validate the prognostic significance of Siglec‐15 and to investigate its regulatory mechanisms in this disease.

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