TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylation.

Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 improves outcomes across multiple malignancies, yet resistance to immune checkpoint blockade remains common. Here, we identify HILPDA as a tumor-intrinsic regulator of immune evasion in breast cancer. HILPDA overexpression increases the infiltration and suppressive activity of regulatory T cells while decreasing the infiltration, activation, and cytotoxicity of CD8+ T cells and natural killer cells, thereby establishing an immunosuppressive tumor microenvironment. Mechanistically, HILPDA binds to HSP90 and protects the transcription factor KLF5 from proteasomal degradation, sustaining fatty acid synthesis and lipid droplet accumulation. The resulting increase in palmitate augments PD-L1 palmitoylation at cysteine 272, enhancing PD-L1 membrane localization and palmitoylation-dependent stability and maintaining inhibitory signaling. We further showed that the E3 ligase TRIM21 mediates K63-linked polyubiquitination of HILPDA and promotes its degradation. In breast cancer models, pharmacologic engagement of TRIM21 with fenretinide decreases PD-L1 palmitoylation, reprograms the tumor microenvironment toward cytotoxic immunity, restores antitumor responses, and improves anti-PD-1 efficacy. Collectively, these results indicate that HILPDA-driven lipogenesis increases PD-L1 palmitoylation, leading to immune evasion and ICB resistance, and TRIM21/HILPDA-targeted combinations are proposed as a therapeutic strategy.