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.