Immune checkpoint blockade (ICB) antibody such as anti-PD-L1 (aPD-L1) activates cytotoxic T cells (CTLs) to combat cancer, but they showed poor efficacy in prostate cancer (PCa). Lysosome-dependent autophagy is utilized by cancer cells to degrade their MHC-I and to lower their vulnerability to TNF-α and CTLs. Lysosomal pH-sensitive polymeric nanoparticle as a drug delivery carrier may also be a novel autophagy inhibitor to boost immunotherapy, but such an important effect has not been investigated. Herein, we developed a unique tumor acidity-activatable macromolecular nanodrug (called P-PDL1-CP) with the poly(2-diisopropylaminoethyl methacrylate) (PDPA) core and the conjugations of both aPD-L1 and long-chain polyethylene glycol (PEG) coating. The PDPA core was demonstrated to disturb lysosome to block the autophagic flux, thus elevating the cancer cell's MHC-I expression and vulnerability to the TNF-α and CTLs. Long-chain PEG facilitated a good tumor accumulation of P-PDL1-CP nanodrug. Furthermore, P-PDL1-CP nanodrug inhibited tumor autophagy, which synergized with aPD-L1 to promote the tumor-infiltrating CTLs and DCs maturation, to elevate intratumoral TNF-α and IFN-γ levels, and to elicit an anti-tumor immune memory effect in mice for PCa growth inhibition with low side effects. This study verified the synergistic anti-PCa treatment between autophagy inhibition and PD-L1 blockade and meantime broadened the application of pH-sensitive macromolecular nanodrug. STATEMENT OF SIGNIFICANCE: A macromolecular nanodrug, comprising the PDPA core and the surface conjugation of both aPD-L1 antibodies and long-chain PEG coating via a tumor acidity-labile α-carboxy-dimethylmaleic anhydride amine bond, was developed. Tumoral acidity triggered the release of aPD-L1 for immunotherapy. Meantime, the charge switch of the remanent nanodrug enhanced the cancer cell uptake of PDPA, which disturbed the lysosomes to inhibit autophagy. This advanced nanodrug promoted the tumor-infiltrating CTLs and DCs maturation, elevated the intratumoral TNF-α and IFN-γ levels, and elicited the robust anti-tumor immune memory effect. This study demonstrated that the pH-sensitive PDPA macromolecule could serve as a carrier for the aPD-L1 delivery and as an efficient autophagy inhibitor to boost the immunotherapy of prostate cancer.