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Immune checkpoint inhibitors (ICIs) show limited efficacy, but some patients regain immunotherapy sensitivity post\u2010TKI. Non\u2010invasive monitoring to identify responders and understand persistent immune tolerance is needed. In this study, we prospectively evaluated a novel granzyme B\u2010targeted PET radiotracer,\u00a0\n                    <jats:sup>68<\/jats:sup>\n                    Ga\u2010GZB, in a clinical cohort of NSCLC patients.\u00a0\n                    <jats:sup>68<\/jats:sup>\n                    Ga\u2010GZB PET\/CT accurately visualized early immune responses and stratified patients likely to benefit from immunotherapy. In preclinical models of acquired EGFR\u2010TKI resistance, we tracked dynamic immune reactivity via\u00a0\n                    <jats:sup>68<\/jats:sup>\n                    Ga\u2010GZB PET\/CT. Single\u2010cell transcriptomics and functional validation identified Lgmn\n                    <jats:sup>+<\/jats:sup>\n                    \u00a0macrophages as a highly immunosuppressive subset driving persistent immunotherapy tolerance. Mechanistically, Lgmn\n                    <jats:sup>+<\/jats:sup>\n                    \u00a0macrophages secrete extracellular vesicles (EVs) that deliver Lgmn directly into CD8\n                    <jats:sup>+<\/jats:sup>\n                    \u00a0T cells. Internalized Lgmn recruits the E3 ubiquitin ligase Chip, initiating the ubiquitination and proteasomal degradation of the glycolytic enzyme Eno1. This cascade severely impairs CD8\n                    <jats:sup>+<\/jats:sup>\n                    \u00a0T cell glycolysis, ultimately leading to CD8\n                    <jats:sup>+<\/jats:sup>\n                    \u00a0T cell exhaustion. Furthermore, we demonstrate that targeting of Lgmn synergizes with PD\u20101 blockade to reactivate anti\u2010tumor immunity in TKI\u2010resistant models. Thus,\u00a0\n                    <jats:sup>68<\/jats:sup>\n                    Ga\u2010GZB PET\/CT provides a non\u2010invasive platform to stratify immunotherapy responses, and targeting Lgmn represents a novel combination strategy for EGFR\u2010TKI\u2010resistant NSCLC.\n                  <\/jats:p>","DOI":"10.1002\/advs.77837","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:45:33Z","timestamp":1789620333000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Granzyme B PET Imaging Reveals Lgmn\n                    <sup>+<\/sup>\n                    Macrophage\u2010Mediated Immune Evasion and Guides Immunotherapy in EGFR\u2010TKI\u2010Resistant NSCLC"],"prefix":"10.1002","author":[{"given":"Dongliang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine Shanghai Cancer Center Fudan University  Shanghai China"},{"name":"Department of 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