A CD68-expressing tissue-homing subset in peripheral CD8+ T cells predicts response to anti-PD-1 therapy in lung cancer

Background T-cell function is regulated by immunometabolism, and lysosomes are signaling hubs. CD68 (LAMP4), traditionally regarded as a monocyte/macrophage marker, has been largely neglected in T cell biology. We aimed to assess the link between CD68 expression in T cells and anti-PD-1 response in lung cancer, and its potential as an early dynamic biomarker in peripheral blood CD8 + T cells. Methods We analyzed transcriptomic (GSE126044, GSE135222, GSE166449) and single-cell (GSE207422) data from anti-PD-1-treated lung cancer cohorts to identify lysosome related pathways and key genes, validated with peripheral blood CD8 + T cell data (GSE111414). Prospectively, we enrolled lung cancer patients receiving anti-PD-1 therapy, collecting peripheral blood at baseline and week 3. Flow cytometry measured CD68 in CD8 + T cells and subsets, assessing association with response, progression-free survival (PFS), and functional markers (granzyme B, perforin, Ki-67, CD69, IFN-γ, IL-1β). Results Responders showed enrichment of lysosome pathways and upregulation of 8 lysosome related genes including CD68, positively correlated with monocyte and T cell infiltration. Single-cell data linked CD68 expression in T cell to favorable response. After one cycle, the proportion of CD8 + CD68 + T cells was lower in non-responders ( P<0.05 ), with AUC 0.803 ( P=0.044 ) and cutoff 1.015%, stratifying PFS ( P=0.0225 ). CD68 was highest in naïve T cells at baseline, but decreased across subsets after treatment in non-responders (all P<0.01 ). Functionally, compared with CD8 + CD68 - T cells, CD8 + CD68 + T cells exhibited lower expression of granzyme B and perforin but higher expression of Ki-67, CD69, IFN-γ, and IL-1β (all P<0.001 ), suggesting a CD8 + T cell state characterized by lower cytotoxicity and enhanced proliferative and cytokine producing capacities, accompanied by a tissue residency associated phenotype. Conclusion CD8 + CD68 + T cells exhibit lower cytotoxicity but greater proliferative and cytokine producing capacities, together with a tissue residency associated phenotype, suggesting a precursor-like state. Low CD68 expression in tumor-infiltrating T cells and the post-treatment reduction of CD68 expression in peripheral blood CD8 + T cells are associated with resistance to anti-PD-1 therapy in lung cancer. These findings suggest that CD8 + CD68 + T cells may serve as a potential early dynamic immune biomarker for monitoring and assessing response to anti-PD-1 therapy in lung cancer.