Combined PARP14 Inhibition and PD-1 Blockade Promotes Cytotoxic T Cell Quiescence and Modulates Macrophage Polarisation in Relapsed Melanoma

Programmed Cell Death 1 (PD-1) signalling blockade is effective in restoring immune surveillance and treating melanoma. However, immune homeostatic mechanisms driven by chronic interferon-gamma (IFNγ) signalling in melanoma cells reduce efficacy, leading to persistent immune evasion and the development of acquired treatment resistance. Previously, we demonstrated that poly ADP ribosyl polymerase 14 (PARP14), encoded by an IFNγ-responsive gene, mediates IFNγ-driven resistance, as inhibition of PARP14 prolonged responsiveness to PD-1 blockade in preclinical models. Nevertheless, inhibition of PARP14 alone was insufficient to fully restore immune clearance, suggesting the presence of redundant resistance mechanisms. The findings here reveal a robust PARP14 catalytic inhibitor (PARP14i) gene signature associated with improved patient survival. We further elucidate the response and adaptation of the immune infiltrate and melanoma cells to PARP14 inhibition using preclinical models. Combining PARP14i with PD-1 blockade therapy revitalised cytotoxic T cells, driving them into a quiescent state while reducing alternatively activated macrophages and increasing pro-inflammatory memory macrophages. Despite this initial enhancement of immune responses through combination therapy, adaptive resistance mechanisms emerged within tumour cells, engaging alternative exhaustion pathways. Our findings indicate that this novel combination therapy leaves immune cells primed for further therapeutic intervention, offering a strategy to address resistance development and optimise treatment outcomes comprehensively.