Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO‐Mediated Immune Escape

Abstract

Breaking immunosuppressive tumor microenvironment (TME) has unique effects on inhibiting tumor growth and recurrence. Here, an endoplasmic reticulum (ER) targeted PdPtCu nanozyme (PNBCTER) is prepared to boost immunotherapy. First, PNBCTER has three kinds of enzyme activities, including catalase (CAT), glutathione oxidase (GSHOx), and peroxidase (POD)‐like activities, which can reshape the TME. Second, PNBCTER kills tumor cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Third, guided by TER, PNBCTER not only realizes the combination therapy of PDT, PTT and chemodynamic therapy (CDT), but also damages the ER of tumor cells and actives antitumor immune response, which breaks through the immune blockade of TME. Finally, the NLG919 blocks the tryptophan/kynurenine immune escape pathway and reverses the immunosuppressive TME. The strategy that reshaping the TME by enzyme catalysis and breaking immunosuppression provides a novel way for the application of combination therapy in tumor.

Transition-Metal-Based Nanozymes: Synthesis, Mechanisms of Therapeutic Action, and Applications in Cancer Treatment

“…Nevertheless, practical applications of immunotherapy often encounter challenges including low efficacy in inducing immune responses and potential effects related to immunity regulation. 237,238 Fortunately, nanozymes with intrinsic enzyme-like activity have emerged as promising agents capable of reversing the immunosuppressive microenvironment in vivo, thereby addressing the limitations associated with conventional immunotherapy. 239 For example, 240 The resulting DNA damage triggered cGAS-mediated production of 2′,3′-cGAMP, which subsequently activated STING, thereby achieving immune modulation within the tumor microenvironment.…”

“…Immunotherapy aims to enhance antitumor responses by engaging both innate and adaptive immune systems through strategies such as administering immune checkpoint inhibitors like anti-PD-1 or anti-PD-L1 antibodies. Nevertheless, practical applications of immunotherapy often encounter challenges including low efficacy in inducing immune responses and potential effects related to immunity regulation. , Fortunately, nanozymes with intrinsic enzyme-like activity have emerged as promising agents capable of reversing the immunosuppressive microenvironment in vivo , thereby addressing the limitations associated with conventional immunotherapy . For example, Zhang et al reported a Co,N-doped carbon dot exhibiting POD-like activity capable of catalyzing H 2 O 2 to generate ROS and induce DNA damage .…”

PdCu nanoparticles with multienzymatic activity to treat tumors through the synergistic photothermal and chemodynamic therapy

“…Nanozymes, that is, nanomaterials containing enzyme-like activity [18][19][20][21], have grown quickly and are now frequently employed in the field of tumor research [22][23][24]. Precious metal nanozymes are a kind of nanomaterials containing noble metals elements (Au, Ag, Pt, Pd, etc) [25][26][27][28][29], which generally have extensive absorption spectrum and excellent photothermal performance, endowing them with the potential of photothermal agent for PTT [30].…”

A Porous Organic Framework‐Based Nanoplatform for Directional Destruction on Endoplasmic Reticulum to Enhance Tumor Immunotherapy

“…[14][15][16][17][18] Furthermore, endoplasmic reticulum (ER) stress would induce ICD effectively, where dying tumor cells release damage-associated molecular patterns (DAMPs), such as calreticulin (CRT), adenosine triphosphate (ATP), and high mobility group box 1 (HMGB1). [19][20][21][22] Thence, ER stress is a crucial factor to determine the efficiency of immunotherapy.…”