Targeting N6-methyladenosine reader YTHDF1 promotes second near-infrared Nano-Photothermal immunotherapy

Photothermal immunotherapy triggered by near-infrared light in the second biowindow (NIR-II) holds great promise for cancer treatment due to its effective ablation of primary tumor with deeper tumor penetration and abscopal effect on distant metastases. However, there are still crucial issues to be addressed including the ineffective immune cell activation, failure to mount a sufficient and lasting anti-tumor response. N6-methyladenosine (m6A)-mediated epigenetic therapeutics is an emerging field in combining with immunotherapy. Here, a nano-epigenetic therapeutic platform (GNR-siYTH1) is rational designed. GNR-siYTH1 consisted of a nuclear localization signal peptide-conjugated PEI-PLA polymer-coated gold nanorod and small interfering RNA targeting YTHDF1, a “reader” of m6A mRNA modification. Targeting YTHDF1 improved photothermal immunotherapy via two epitranscriptomic mechanisms: 1) reduction of translation of HSP70, which lowered the thermo-resistance of tumor cells and enhanced photothermal performance, and 2) inhibition of antigen degradation in the dendritic cells by restricting the expression of lysosomal proteases, which improved cross-presentation and cross-priming of CD8+ T cells. The GNR-siYTH1 platform in combination with PD-L1 checkpoint blockade effectively inhibited primary tumor growth, suppressed metastasis and prevented tumor recurrence. This study presents a new strategy for combined m6A mRNA modulators with photothermal therapy for development of nano-epigenetic immunotherapy.