Tumor-intrinsic NLRX1-mediated mitophagy drives immune evasion through extracellular lipid remodeling

Mitophagy is emerging as a key regulator of tumor progression, yet its role in immune evasion remains poorly understood. Here, bioinformatic analyses of human and mouse tumors, together with mitophagy reporter imaging, reveal an inverse association between tumor-intrinsic mitophagy and CD8 + T cell infiltration. High mitophagy signatures correlate with poor immunotherapy responses and unfavorable clinical outcomes. We identify NOD-like receptor family member X1 (NLRX1) as the key tumor-intrinsic mitophagy receptor that suppresses CD8 + T cell function. High NLRX1 expression is associated with poorer outcomes in melanoma or lung cancer patients, particularly those receiving immunotherapy. Mechanistically, loss of NLRX1 increases cell-surface CD36 expression and tumor-cell uptake of polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), thereby reducing extracellular DHA levels and relieving DHA-mediated suppression of CD8 + T cell activation. Re-expression of wild-type NLRX1, but not an LC3-interacting region deletion mutant, restores extracellular DHA levels and T cell suppression, supporting a mitophagy-dependent mechanism. In mouse melanoma models, tumor-cell NLRX1 deficiency suppresses tumor growth in a CD8 + T cell-dependent manner and enhances anti-PD-1 efficacy. Conversely, oral DHA supplementation promotes tumor growth in mice receiving OT-I adoptive transfer, accompanied by increased lipid peroxidation and reduced CD8 + T cell effector function. Together, these findings link NLRX1-dependent mitophagy to tumor-cell lipid uptake, extracellular DHA levels and antitumor immunity, highlighting this pathway as a potential target for improving cancer immunotherapy.