Immune checkpoint inhibitors (ICIs) have profoundly reshaped the treatment paradigm for non-small cell lung cancer (NSCLC). Despite these advancements, primary and secondary resistance to ICIs remain prevalent challenges in managing advanced NSCLC. Recent studies have highlighted the significant role of the tumor microenvironment (TME) in modulating treatment responses. This review aims to comprehensively examine the interactive roles of immune/stromal cells-such as T cells, B cells, neutrophils, macrophages, and CAFs within the TME, elucidating how these diverse cellular interactions contribute to immunotherapy resistance. It focuses on the dynamic interactions among diverse cell types such as the varying states of T cells under the influence of TME constituents like immune cells and cancer-associated fibroblasts (CAFs). By exploring the mechanisms involved in the complex cellular interactions, we highlight novel therapeutic targets and strategies aimed at overcoming resistance, thereby enhancing the efficacy of ICIs in NSCLC. Our synthesis of recent research provides critical insights into the multifaceted mechanisms of resistance and paves the way for the development of more effective, personalized treatment approaches.Copyright © 2024. Published by Elsevier B.V.