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Figure 1. TME-driven strategies for Cold-to-Hot tumor transformation in lung cancer. This figure illustrates a comprehensive framework for reprogramming the TME to overcome immunotherapy resistance in lung cancer, enabling cold-to-hot tumor transformation. The central schematic represents the lung TME, encompassing key components and their interconnections, with surrounding annotations detailing targeted therapeutic strategies. Core immune-suppressive cells, including Tregs, MDSCs, and TAMs, act as critical barriers to effective antitumor immunity. Strategies such as depleting or reprogramming these cells aim to restore immune responsiveness. Emerging players, such as NK cells, B cells, DCs, and NETs, are highlighted as potential contributors to immune activation when properly targeted. The ECM and CAFs are identified as physical and biochemical barriers that impede immune infiltration; therapeutic approaches include ECM-degrading enzymes, angiogenesis inhibitors, and CAF reprogramming therapies. Metabolic reprogramming focuses on addressing tumor-induced metabolic dysregulation, including glycolysis, lactate accumulation, and nutrient imbalances, through interventions that enhance mitochondrial function and restore metabolic homeostasis. Cellular communication within the TME, mediated by chemokines and exosomes, reinforces immunosuppressive networks; strategies such as CRISPR-Cas9, neutral sphingomyelinase blockers, and RNA-based exosome editing hold promise for disrupting these interactions. The integrative networks within the TME underscore the dynamic interplay of immune, metabolic, and structural components, necessitating combined approaches. Highlighted therapeutic strategies include immuno-metabolic reprogramming, vascular remodeling, immune co-activation, and next-generation adaptive combinations. This figure provides a unified view of the TME’s complexity and offers insights into multi-modal strategies to reprogram the TME for improved immunotherapy outcomes. TME: Tumor microenvironment; Tregs: regulatory T cells; MDSCs: myeloid-derived suppressor cells; TAMs: tumor-associated macrophages; NK cells: natural killer cells; DCs: dendritic cells; NETs: neutrophil extracellular traps; ECM: extracellular matrix; CAFs: cancer-associated fibroblasts; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-associated protein 9; TCA: tricarboxylic acid.