CCL5 Orchestrates Paradoxical Immune Landscapes in NSCLC: Simultaneous Recruitment of Effector and Suppressor Cells Shapes Immunotherapy Resistance

Background: The chemokine CCL5 exhibits a complex role in cancer immunotherapy, yet its dual immunomodulatory functions in non-small cell lung cancer (NSCLC) remain poorly understood. Methods and Results: Based on a newly analyzed clinical cohort of 33 advanced NSCLC patients receiving anti-PD-1 therapy combined with platinum-based chemotherapy, we found that elevated baseline peripheral blood CCL5 levels significantly predicted shorter overall survival (27.6 months vs. not reached, HR = 2.779, p = 0.038) and a higher incidence of immune-related pneumonitis (p = 0.0072). These clinical observations were supported by the re-analysis of a previously published single-cell RNA sequencing (scRNA-seq) dataset (n = 8), which indicated that high CCL5 expression in peripheral blood T/NK cells was associated with a lower major pathological response (p = 0.029). To explore the underlying mechanisms, we conducted detailed analyses using a large, publicly available tumor scRNA-seq dataset (GSE243013, n = 234). These analyses revealed that high intratumoral CCL5 simultaneously promoted the recruitment of both immune effector cells (CD8+ T cells, NK cells) and immunosuppressive populations (Tregs, MDSCs). This paradoxical immune landscape correlated with elevated immune checkpoint expression and significantly higher TIDE scores (1.47 vs. 0.83, p < 0.001). CellChat and SCENIC network analyses identified intensified T cell–myeloid communication and key transcription factors (e.g., FOXP3, EOMES) mediating this dichotomy. Conclusions: This hypothesis-generating study raises the possibility that CCL5 orchestrates paradoxical immune responses and may serve as a biomarker in NSCLC. Further validation in larger prospective, independent cohorts is required.