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

Background

Programmed Cell Death 1 (PD-1) signaling blockade effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute to immune evasion and acquired resistance. Poly ADP ribosyl polymerase 14 (PARP14), an IFNγ-responsive gene product, partially mediates IFNγ-driven resistance. PARP14 inhibition prolongs PD-1 blockade responses in preclinical models, but fails to achieve full tumour clearance, suggesting the involvement of additional resistance mechanisms

Methods

We identified a robust PARP14 catalytic inhibitor (PARP14i) gene signature and evaluated its association with patient survival. Using preclinical models and single-cell RNA sequencing, we investigated immune and tumour cell adaptations to PARP14 inhibition combined with PD-1 blockade.

Results

Combining PARP14 inhibition and PD-1 blockade suppressed tumour-associated
macrophages while increasing pro-inflammatory memory macrophages. Moreover, this combination mitigated the terminal exhaustion of cytotoxic T cells by inducing a quiescent state, thereby preserving functionality. Despite the enhanced immune responses, tumour cells developed adaptive resistance by engaging alternative immune evasion pathways.

Conclusions

Although adaptive resistance mechanisms re-emerge, PARP14 inhibition combined with PD-1 blockade offers a promising strategy to enhance treatment outcomes and overcome resistance in melanoma, as immune cells are primed for further therapeutic interventions that leverage the quiescent state.