Checkpoint Nano‐PROTACs for Activatable Cancer Photo‐Immunotherapy

Abstract

Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off‐target adverse effects. Herein, checkpoint nano‐proteolysis targeting chimeras (nano‐PROTACs) in combination with photodynamic tumor regression and immunosuppressive protein degradation to block checkpoint signaling pathways for activatable cancer photo‐immunotherapy are reported. These nano‐PROTACs are composed of a photosensitizer (protoporphyrin IX, PpIX) and an Src homology 2 domain‐containing phosphatase 2 (SHP2)‐targeting PROTAC peptide (aPRO) via a caspase 3‐cleavable segment. aPRO is activated by the increased expression of caspase 3 in tumor cells after phototherapeutic treatment and induces targeted degradation of SHP2 via the ubiquitin‐proteasome system. The persistent depletion of SHP2 blocks the immunosuppressive checkpoint signaling pathways (CD47/SIRPα and PD‐1/PD‐L1), thus reinvigorating antitumor macrophages and T cells. Such a checkpoint PROTAC strategy synergizes immunogenic phototherapy to boost antitumor immune response. Thus, this study represents a generalized PROTAC platform to modulate immune‐related signaling pathways for improved anticancer therapy.

Melanin-Based Immunoregulatory Nanohybrids Enhance Antitumor Immune Responses in Breast Cancer Mouse Model

“…As a promising clinical strategy to fight cancer, immunotherapy has attracted tremendous attention while nanoparticles have demonstrated great potential in eliciting and boosting anticancer immune responses. − Nanoparticles are widely employed to induce immunogenic cell death (ICD) of tumor cells through various approaches to recruit T cells and stimulate the antitumor immunity. − Among them, natural melanin nanoparticles (MNPs) extracted from living organisms demonstrate great potential due to their intriguing physicochemical and biological properties, and ICD could be induced by the intrinsic photothermal property . In addition, MNPs were found to reprogram tumor-associated macrophages (TAMs) through the activation of the mitogen-activated protein kinase (MAPK) signaling pathway .…”

The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy

“…Targeting SHP2, a protein tyrosine phosphatase, by PROTACs is useful for cancer immunotherapy partly via regulation of several signaling pathways, such as PD-1/PD-L1, PI3K/AKT, RAS/ERK, JAK/STAT pathways ( 99 ). Moreover, nano-PROTACs targeting SHP2 inactivated the CD47/SIRPα and PD-1/PD-L1 pathways, contributing to reinvigoration of T cells and macrophages as well as promotion of antitumor immune response ( 100 ). Recently, peptide-PROTACs targeting PD-1/PD-L1 degradation were designed and exhibited high potential activity to degrade PD-1/PD-L1 in tumor cells, which caused tumor cell death ( 101 ).…”

Targeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer

“…In 2022, the other two nano-PROTAC polymers (cyclooxygenase 1/2 (COX-1/2)-targeting nano-PROTAC and Src homology 2 domain-containing phosphatase 2 (SHP2)-targeting nano-PROTAC) for activatable cancer immunotherapy were developed, and significantly enhanced antitumor immunity. [25,88]…”