Defining PON2 as a metabolic immune checkpoint of iron redox balance and ferroptotic defense in lung adenocarcinoma

Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer, survives persistent oxidative stress through adaptive remodeling of mitochondrial and metabolic networks. Redox equilibrium therefore dictates whether LUAD cells withstand oxidative pressure or succumb to ferroptosis; a lipid peroxidation driven form of regulated cell death¹. The mitochondrial enzyme paraoxonase 2 (PON2) functions as an intrinsic antioxidant that detoxifies lipid peroxides and sustains respiratory integrity². In LUAD, chronic activation of NRF2 (NFE2L2); frequently through loss of KEAP1, drives constitutive antioxidant programs involving glutathione synthesis and GPX4, FSP1, and PON2 dependent ferroptosis defenses³ - ⁴. These redox insulated states promote metabolic resilience, suppress immunogenic cell death (ICD), and reinforce immune excluded tumor architectures⁴ - ⁵.We identify PON2 as a metabolic immune checkpoint that integrates NRF2/KEAP1 driven redox adaptation with ferroptosis resistance and immune escape. Integrative genomic, spatial, and functional analyses reveal that PON2 expression stratifies LUAD by ferroptotic vulnerability; aligns with antioxidant and iron handling networks (TFRC, FTH1, FTL); and that PON2 loss increases lipid peroxide burden, disrupts mitochondrial flux, and heightens ICD signaling in patient derived LUAD models.These findings delineate how PON2 enforces ferroptosis resistance and immune invisibility, revealing targetable redox metabolic bottlenecks that could be leveraged to restore tumor immunogenicity⁶.