Despite compelling preclinical and epidemiological evidence (e.g., reduced lung cancer incidence in the CANTOS trial), IL-1β inhibition with canakinumab failed to achieve the expected therapeutic effect in the Phase III clinical trials (CANOPY series) of non-small cell lung cancer (NSCLC). This perspective analyzes the disconnect between mechanistic promise and clinical outcomes. IL-1β drives NSCLC progression by promoting immunosuppression, angiogenesis, and metastasis. However, CANOPY-2 showed no overall survival (OS) benefit, though a trend emerged in patients with an elevated baseline of high-sensitivity C-reactive protein (hs-CRP). Similarly, CANOPY-1 and adjuvant CANOPY-A missed primary endpoints for progression-free survival (PFS) and disease-free survival (DFS), respectively. These failures highlight limitations of IL-1 monotherapy in advanced, immunosuppressive microenvironments and underscore inadequate patient selection. We propose that IL-1 antagonism retains therapeutic potential but requires refined strategies: biomarker-driven enrichment (e.g., inflammation signatures like hs-CRP), rational combinatorial regimens informed by successful multi-target agents (e.g., cadonilimab), and early-stage intervention. Repositioning IL-1 blockers through precision approaches could unlock their value in immuno-oncology.