Background <p>We previously demonstrated that immune cells expressing α-synuclein (SNCA) are dramatically increased in peripheral blood of patients with gastric cancer (GC), but rarely in healthy donors, and that blocking SNCA is significantly effective even in anti-PD1-resistant mouse tumor models with increased SNCA⁺ cells. This suggests that the increased SNCA⁺ cells are involved in resistance to anti-PD1 therapy. However, the relationship between SNCA⁺ cell levels and anti-PD1/PDL1 therapeutic efficacy in GC remains to be determined in clinical settings.</p> Methods <p>In the WJOG10417GTR study, peripheral blood cells collected from advanced GC patients before and one month after nivolumab monotherapy were analyzed for several SNCA⁺ cell populations by flow cytometry, and the relationship between the levels and patient prognosis was statistically analyzed.</p> Results <p>High levels of SNCA⁺ cells, particularly the myeloid subset, before and after treatment were significantly associated with shorter progression-free survival and overall survival. Patients with low SNCA⁺ cell levels survived for a long time without disease progression, indicating durable responders.</p> Conclusion <p>These suggest that SNCA⁺ cells are significant poor prognostic factors in nivolumab therapy for advanced GC. Targeting SNCA may be a promising strategy to improve clinical outcomes in anti-PD1/PDL1 therapy for GC.</p>