As a major component of tumor infiltration, tumor-associated macrophages (TAMs) primarily promote the M2 phenotype of tumors in the tumor microenvironment. Additionally, the overexpression of anti-phagocytic molecules in TAMs facilitates tumor cell evasion of TAMs’ phagocytic arrest. Therefore, there is an urgent need to develop a reliable strategy to reprogram TAMs for more effective anti-tumor outcomes. In this study, innovative inhalable bioorthogonal gene-editable microparticles (SPR) have been engineered that reprogram TAMs for lung cancer therapy based on spike-covered sunflower sporopollenin exine capsules (SECs). These microparticles utilize SECs as delivery vehicles, with reduced palladium (Pd) nanoparticles on their surface carrying CRISPR/Cas9 lipid nanoparticles (LNP-RNPs) that specifically knock down the anti-phagocytic SIRPα gene on TAMs. The SPR microparticles employ a tripartite strategy to reprogram the TAMs: the physical stimulation through pollen spikes, the production of a Toll-like receptor 7 agonist (imiquimod, IMD) via Pd-mediated bioorthogonal catalysis, and the employment of CRISPR/Cas9 gene editing. In an orthotopic mouse model, the inhalation of SPR microparticles not only reprograms macrophages efficiently but also bolsters their tumor-fighting abilities. Notably, the cured mice show no signs of recurrence even upon re-exposure to the tumor, indicating a long-lasting anti-tumor effect.