Advancements in Stimulus-Responsive Co-Delivery Nanocarriers for Enhanced Cancer Immunotherapy

Abstract

Cancer immunotherapy has emerged as a novel therapeutic approach against tumors, with immune checkpoint inhibitors (ICIs) making significant clinical practice. The traditional ICIs, PD-1 and PD-L1, augment the cytotoxic function of T cells through the inhibition of tumor immune evasion pathways, ultimately leading to the initiation of an antitumor immune response. However, the clinical implementation of ICIs encounters obstacles stemming from the existence of an immunosuppressive tumor microenvironment and inadequate infiltration of CD8⁺T cells. Considerable attention has been directed towards advancing immunogenic cell death (ICD) as a potential solution to counteract tumor cell infiltration and the immunosuppressive tumor microenvironment. This approach holds promise in transforming "cold" tumors into "hot" tumors that exhibit responsiveness to antitumor. By combining ICD with ICIs, a synergistic immune response against tumors can be achieved. However, the combination of ICD inducers and PD-1/PD-L1 inhibitors is hindered by issues such as poor targeting and uncontrolled drug release. An advantageous solution presented by stimulus-responsive nanocarrier is integrating the physicochemical properties of ICD inducers and PD-1/PD-L1 inhibitors, facilitating precise delivery to specific tissues for optimal combination therapy. Moreover, these nanocarriers leverage the distinct features of the tumor microenvironment to accomplish controlled drug release and regulate the kinetics of drug delivery. This article aims to investigate the advancement of stimulus-responsive co-delivery nanocarriers utilizing ICD and PD-1/PD-L1 inhibitors. Special focus is dedicated to exploring the advantages and recent advancements of this system in enabling the combination of ICIs and ICD inducers. The molecular mechanisms of ICD and ICIs are concisely summarized. In conclusion, we examine the potential research prospects and challenges that could greatly enhance immunotherapeutic approaches for cancer treatment.

Keywords: antitumor therapy; co-delivery; immune-checkpoint inhibitors; immunogenic cell death; stimulus-responsive nanocarriers.

Figure 1

Mechanisms of ICD (by Figdraw).

Figure 2

Mechanism of PD-1/PD-L1 inhibitors (by Figdraw).

Figure 3

Schematic diagram of the release of exogenous stimulus-responsive nanocarriers under stimulus. (A) Photo-responsive nanocarriers. (B) Magnetic-responsive nanocarrier. (by Figdraw).

Figure 4

Schematic diagram of the release of endogenous stimulus-responsive nanocarriers under stimulus. (A) Enzyme-responsive nanocarriers. (B) pH-responsive nanocarriers. (C) Redox-responsive nanocarriers. (by Figdraw).

Figure 5

Schematic diagram of the release of dual-stimulus-responsive nanocarriers under stimulus. (A) pH and redox dual-responsive nanocarriers. (B) pH and light dual-responsive nanocarriers. (C) pH and enzyme dual-responsive nanocarriers. (by Figdraw).