AZD4635 Targets cAMP/CREB Axis to Salvage PARPi-Induced Immune Evasion and Enhance Antitumor Efficacy in Ovarian Cancer.

Background/Objectives: Poly(ADP-ribose) polymerase inhibitors (PARPis) have significantly transformed the treatment landscape for ovarian cancer; however, their clinical efficacy is often limited by poor response rates and the emergence of resistance. Recent studies have revealed that in ovarian cancer cells resistant to PARPi, the expression levels of adenosine receptors are upregulated. Accumulation of adenosine activates adenosine A2A receptor (A2AR) on immune cells, leading to immune suppression and immune escape. We hypothesize that this is a key factor limiting the efficacy of PARPi and driving the development of resistance. Therefore, the rational combination of PARPi with A2AR antagonists (A2ARas) may represent a highly promising anticancer strategy. Methods: To assess the effects of the PARPi AG14361 and the A2ARa AZD4635 on ovarian cancer growth and the immune microenvironment, we conducted in vitro and in vivo experiments and utilized single-cell RNA sequencing (scRNA-seq) to construct a high-resolution immune landscape. Results: AG14361 significantly inhibited ovarian cancer growth both in vitro and in vivo, accompanied by the accumulation of cyclic adenosine monophosphate (cAMP) and activation of the cAMP/cAMP response element-binding protein (CREB) pathway in mouse cells and tumor tissues. However, compared to monotherapy, the combination of AG14361 and AZD4635 significantly enhanced antitumor activity by inhibiting cAMP accumulation and the cAMP/CREB pathway. More importantly, the combination therapy of PARPi and A2ARa reduced the infiltration of immunosuppressive cells (such as regulatory T cells and M2 macrophages) while increasing the infiltration of cytotoxic T cells and granzyme B-positive cells, thereby creating a more favorable immune microenvironment for tumor clearance. Single-cell analysis revealed distinct functional subpopulations of macrophages and T cells, highlighting the complexity of immune heterogeneity and the potential for targeting specific immune cell subpopulations to enhance therapeutic efficacy. Conclusions: These findings suggest that the combination therapy of PARPi and A2ARa is a highly promising strategy that overcomes PARPi-induced immune escape by targeting the cAMP/CREB axis, thereby synergistically enhancing antitumor effects and holding promise as an effective treatment for solid tumors.