EGFR-mutant non–small cell lung cancer (NSCLC) initially responds well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), yet resistance is nearly inevitable and responses to immune checkpoint inhibitors (ICIs) remain limited. In a retrospective cohort of 57 patients with advanced EGFR-mutant NSCLC treated with nivolumab or pembrolizumab, the objective response rate was 12.3%, although responses were concentrated in a small subgroup with concurrent high PD-L1 expression and dense intratumoral CD8⁺ immune-cell infiltration. Emerging evidence links these outcomes to chemokine-network dysregulation that alters immune trafficking and spatial organization. Oncogenic EGFR signaling shifts chemokine networks away from effector T-cell recruitment and toward regulatory and myeloid-cell accumulation, thereby promoting immune exclusion and treatment adaptation. CXCL12–CXCR4 signaling, stromal barriers, and defective organization of tertiary lymphoid structures further reinforce immune exclusion and ICI resistance. Under EGFR-TKI pressure, chemokine programs evolve dynamically, permitting transient immune entry while sustaining drug tolerance, EMT-associated persistence, and myeloid-supported resistance. However, most proposed chemokine mechanisms remain supported predominantly by preclinical or clinical-correlative evidence, and their causal, temporal, and predictive relevance in patients remains unresolved. Defining these circuits may guide biomarker-driven combinations to convert immune-excluded tumors into immune-permissive states and to prolong disease control through rational TKI-, ICI-, and chemokine-targeted therapeutic strategies.