Tumor intrinsic regulation of PD-L1 and of interferon Type I via an SLC25A1-driven mitochondrial pathway, influences the anti-tumor immune response

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet variable patient responses highlight the need to better define tumor-intrinsic regulators of immune sensitivity. Here, we identify the mitochondrial citrate carrier SLC25A1 as a determinant of ICI responsiveness through a dual regulation of type I interferon (IFN-I) signaling and of PD-L1 expression. SLC25A1 promotes a mitochondrial-to-nuclear retrograde signaling via cytosolic accumulation of mitochondrial DNA, activation of the cGAS-STAT1 axis, and establishment of a virus mimicry state that enhances the IFN-I response. This activation is enriched in cancer stem cell populations, linking SLC25A1 to immune evasion and tumor progression. Moreover, SLC25A1 also regulates PD-L1 protein levels through a newly identified fumarate-Keap1-PD-L1 axis, whereby fumarate destabilizes Keap1, leading to PD-L1 up-regulation. In vivo, tumors expressing high levels of SLC25A1 exhibit an inflammatory microenvironment and increased sensitivity to PD-L1 blockade, but accelerated growth in the absence of anti-PD-L1 treatment. These findings position SLC25A1 as a novel regulator of mitochondrial-driven immune signaling and PD-L1 stability, and suggest that SLC25A1 exploits PD-L1 signaling to evade immune surveillance, while at the same time creating an intrinsic tumor vulnerability to checkpoint blockade. Thus, SLC25A1 may serve both as a biomarker of response and as a target to enhance the efficacy of immunotherapy.