Pentose phosphate pathway fuels cGAS-STING signalling to boost function of intratumoral conventional dendritic cells

Tumors employ diverse mechanisms to impair conventional dendritic cell (cDC) function within the tumor microenvironment, yet the underlying processes remain unclear. Here, we demonstrate that pentose phosphate pathway (PPP) reduction in late-stage intratumoral cDCs compromises their function. Both pharmacological and genetic inhibition of the PPP attenuate cDC-mediated antitumor responses. Conversely, PPP augmentation restores late-stage intratumoral cDC antitumor capacity. PPP deficiency in cDCs enhances the immune checkpoint PD-L1 expression level, and combining cDC-specific PPP potentiation with immune checkpoint blockade synergistically enhances immunotherapy efficacy. Mechanistically, PPP activation fuels purine metabolism, thereby increasing ATP and GTP levels required for 2’3’-cGAMP synthesis, ultimately promoting cGAS-STING signaling and STING-dependent cDC antitumor responses. The PPP is associated with STING-dependent cDC activities in tumor tissues from female patients with breast cancer. Collectively, our findings establish PPP as an intrinsic metabolic checkpoint in STING-mediated cDC antitumor immunity, and suggest targeting PPP in cDCs as a promising cancer immunotherapy strategy. Conventional dendritic cells (cDCs) are essential to generate effective anti-tumor immune responses; however, they are often dysfunctional within the tumor microenvironment. Here the authors report that the impaired function of cDCs in late-stage tumors is associated with a reduction of pentose phosphate pathway (PPP), suggesting strategies to augment PPP as a therapeutic option to increase cDC-mediated anti-tumor response.