NADPH Selective Depletion Nanomedicine-Mediated Radio-Immunometabolism Regulation for Strengthening Anti-PDL1 Therapy against TNBC.

Anti-PD(L)1 immunotherapy recently arises as an effective treatment against triple-negative breast cancer (TNBC) but is only applicable to a small portion of TNBC patients due to the low PD-L1 expression and the immunosuppressive tumor microenvironment (TME). To address these challenges, a multifunctional "drug-like" copolymer that possesses the auto-changeable upper critical solution temperature and the capacity of scavenging reduced nicotinamide adenine dinucleotide phosphate (NADPH) inside tumor cells is synthesized and employed to develop a hypoxia-targeted and BMS202 (small molecule antagonist of PD-1/PD-L1 interactions)-loaded nanomedicine (BMS202@HZP NPs), combining the anti-PD-L1 therapy and the low-dose radiotherapy (LDRT) against TNBC. In addition to the controlled release of BMS202 in the hypoxic TNBC, BMS202@HZP NPs benefit the LDRT by upregulating the pentose phosphate pathway (PPP, the primary cellular source for NADPH) of TME whereas scavenging the NADPH inside tumor cells. As a result, the BMS202@HZP NPs-mediated LDRT upregulate the PD-L1 expression of tumor to promote anti-PD-L1 therapy response while reprogramming the immunometabolism of TME to alleviate its immunosuppression. This innovative nanomedicine-mediated radio-immunometabolism regulation provides a promising strategy to reinforce the anti-PD-L1 therapy against TNBC.