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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 &lt; 0.001). CellChat and SCENIC network analyses identified intensified T cell\u2013myeloid 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.<\/jats:p>","DOI":"10.3390\/cancers18081271","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T15:14:12Z","timestamp":1776352452000},"page":"1271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CCL5 Orchestrates Paradoxical Immune Landscapes in NSCLC: Simultaneous Recruitment of Effector and Suppressor Cells Shapes Immunotherapy Resistance"],"prefix":"10.3390","volume":"18","author":[{"given":"Shuzhan","family":"Li","sequence":"first","affiliation":[{"name":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Tianjin\u2019s Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China"},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Tianjin\u2019s Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China"},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Tianjin\u2019s Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China"},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Hui","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Tianjin\u2019s Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China"},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Tianjin\u2019s Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China"},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Tianjin\u2019s Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China"},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiubao","family":"Ren","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Tianjin\u2019s Clinical Research Center for Cancer, Tianjin 300060, China"},{"name":"Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China"},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"},{"name":"Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA A Cancer J. 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