Targeting phosphodiesterase 10A by ADT-030 normalizes the tumor immune microenvironment by inhibiting RAS-MAPK signaling in both cancer cells and myeloid-derived suppressor cells

Phosphodiesterase 10A (PDE10A), a cyclic nucleotide-degrading enzyme, is overexpressed in various human cancers. While PDE10A inhibition using small-molecule inhibitors or gene silencing suppresses tumor growth in xenograft models, its precise mechanism of action and immunological impact remain unclear. Here, we report that ADT-030, a novel PDE10A inhibitor, exhibits potent cytotoxicity against a broad range of murine tumor cell lines through suppression of RAS/MAPK signaling in both cancer cells and myeloid-derived suppressor cells (MDSCs). ADT-030 is orally bioavailable and effectively suppresses tumor growth in multiple syngeneic mouse models. Notably, its efficacy is significantly diminished in immunodeficient mice or upon CD8+ T cell depletion, highlighting a critical dependence on host immunity. The immunopotentiating effects of ADT-030 are further evidenced by its synergy with anti-PD-1 therapy, its ability to induce immunogenic tumor cell death and promote dendritic cell (DC) maturation in vitro, and its reliance on cDC1 to elicit antitumor effects in vivo. Comprehensive immune profiling in the 4T1 triple-negative breast cancer model, both in orthotopic and metastatic settings, revealed that ADT-030 selectively reduces tumor-associated neutrophils while restoring the presence and function of CD8+ T cells. These findings highlight PDE10A inhibition as a multi-faceted strategy that not only disrupts tumor-intrinsic oncogenic signaling but also reshapes the tumor immune microenvironment to unleash antitumor immunity.