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Background: Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) has emerged as a novel immunotherapy candidate, which deserves a comprehensive investigation in lung adenocarcinoma (LUAD). Methods: Multiplex fluorescence‐based immunohistochemistry was conducted to assess Siglec-15 expression and tumor-infiltrating immune cells in LUAD from Tianjin cohort, with validation cohorts Xinchao 04 and 07. Results: This study revealed that Siglec-15 was positively correlated with CD8+ T cells and tumor-associated macrophages (TAMs) infiltration, but CD8+ T cells were mostly infiltrated in the stroma area, not in the tumor area. Spatially, fewer CD8+ T cells surrounded Siglec-15+ tumor cells in PD-L1− cells, and more TAMs surrounded Siglec-15+ tumor cells in PD-L1−/+ cells. Siglec-15+ TAMs infiltrated with more CD8+ T cells, and were closer to CD8+ T cells than Siglec-15− TAMs and Siglec-15+ tumor cells. Siglec-15+ TAMs infiltrated with more Tregs and were closer to Tregs than Siglec-15+ tumor cells. Siglec-15+ tumor cells or TAMs reversed CD8+ T cells prognosis value, and enhanced the prognosis value of Tregs and TAMs. The immunotyping based on Siglec-15 and CD8A / CD8+ T cells revealed that patients with high CD8A and Siglec-15 expression exhibited immune activation. Patients with low CD8A expression / CD8+ T cells infiltration and Siglec-15 overexpression were related to the activation of immunosuppressive signature and metabolism-related pathway, and infiltrated with more TAMs. Conclusions: We revealed the distinct characteristics between Siglec-15+ tumor cells and TAMs in relation to CD8+ T cells, and a unique relationship between Siglec-15 and immunosuppressive TIME in LUAD, which may provide potential value for anti-Siglec-15 therapy. [ABSTRACT FROM AUTHOR]