Near-infrared　(NIR)　light-mediated　photodynamic　therapy　(PDT),　especially　based　on　lanthanide-doped　upconversion　nanocrystals　(UCNs),　have　been　extensively　investigated　as　a　promising　strategy　for　effective　cellular　ablation　owing　to　their　unique　optical　properties　to　convert　NIR　light　excitation　into　multiple　short-wavelength　emissions.　Despite　the　deep　tissue　penetration　of　NIR　light　in　living　systems,　the　therapeutic　efficiency　is　greatly　restricted　by　insufficient　oxygen　supply　in　hypoxic　tumor　microenvironment.　Moreover,　the　coexistent　tumor-associated　macrophages　(TAMs)　play　critical　roles　in　tumor　recurrence　during　the　post-PDT　period.　Herein,　we　developed　a　unique　photosensitizer-loaded　UCNs　nanoconjugate　(PUN)　by　integrating　manganese　dioxide　(MnO2)　nanosheets　and　hyaluronic　acid　(HA)　biopolymer　to　improve　NIR　light-mediated　PDT　efficacy　through　attenuating　hypoxia　status　and　synergistically　reprogramming　TAMs　populations.　After　the　reaction　with　overproduced　H2O2　in　acidic　tumor　microenvironment,　the　MnO2　nanosheets　were　degraded　for　the　production　of　massive　oxygen　to　greatly　enhance　the　oxygen-dependent　PDT　efficiency　upon　808　nm　NIR　light　irradiation.　More　importantly,　the　bioinspired　polymer　HA　could　effectively　reprogram　the　polarization　of　pro-tumor　M2-type　TAMs　to　anti-tumor　M1-type　macrophages　to　prevent　tumor　relapse　after　PDT　treatment.　Such　promising　results　provided　the　great　opportunities　to　achieve　enhanced　cellular　ablation　upon　NIR　light-mediated　PDT　treatment　by　attenuating　hypoxic　tumor　microenvironment,　and　thus　facilitated　the　rational　design　of　new　generations　of　nanoplatforms　toward　immunotherapy　to　inhibit　tumor　recurrence　during　post-PDT　period.　©　2018　American　Chemical　Society.