Transformable prodrug nanoplatform via tumor microenvironment modulation and immune checkpoint blockade potentiates immunogenic cell death mediated cancer immunotherapy

Abstract

Rationale: Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Methods: Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist ( D PPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core ( D PPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. Results: D PPA-TRPP/Tab reassembled into a micellar structure in vivo with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by D PPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. In vivo results indicated that D PPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. Conclusion: The study offers potential in tumor eradication via exploiting an “all-in-one” smart polymeric nanoplatform.

Nanomedicine Remodels Tumor Microenvironment for Solid Tumor Immunotherapy

“…The formulation demonstrated notable therapeutic effects on subcutaneous MC38 colorectal cancer tumors and orthotopic 4T1 breast cancer tumors. 48 In addition to sono-sensitive liposomes, several other nanocarriers have been developed for the delivery of ICD inducers, including ultrasound-activated polymers, 49 pH/redox-responsive polymers, 50 reactive oxygen species (ROS)-responsive polymers, 51 dual-responsive polymers to pH and ROS, 52 dual-responsive polymers to pH and glutathione (GSH), 53 and pH-responsive calcium carbonate nanoparticles. 54 These nanocarriers capable of loading and delivering ICD inducers offer diverse strategies for targeted cancer immunotherapy.…”

Polymersomes as Innovative, Stimuli-Responsive Platforms for Cancer Therapy

“…It highlights the encapsulation and efficient release of talabostat (rapidly released at pH 6.8, with or without H 2 O 2 , the cumulative release was as high as 80.9% within 24 h), mesylate, and DOX (cumulative release as high as 93.1% in a pH 5.0 10 mM GSH solution within 24 h) within the tumor, demonstrating significant tumor suppression and immune response activation in vitro and in vivo. Specifically, the study showcases a 60% complete tumor regression ratio in mice, indicating the potential of this “all-in-one” nanoplatform for effective tumor eradication and long-term immune memory against cancer [ 151 ].…”

“…This framework provides a concise overview of how dual-responsive polymersomes can be tailored to enhance cancer therapy's specificity and efficacy. UCNP-PNSP@DOX Ultraviolet + redox DOX Non-small-cell lung cancer -High cell viability against three lung cancer cell lines; -From biochemistry analysis and histopathological results, the nanostructures showed no damage to the heart, liver, spleen, lung, and kidney In mice, a 60% complete tumor regression ratio and a long-term immune memory response were registered [151] There are polymersomes that are both photocrosslinked and sensitive to temperature and pH, used for the codelivery of DOX and PTX [146]. Others include ultraviolet and redox responsiveness for the delivery and release of DOX [148], and redox-and pH-responsive polymersomes containing ferrocene moieties [149].…”

Stimuli-Responsive Polymersomes: Reshaping the Immunosuppressive Tumor Microenvironment

“…A novel tumor TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was developed by Yang et al with conjugating the D-peptide antagonist ( D PPA-1) of programmed death ligand-1 onto the surface and encapsulating talabostat mesylate (Tab), a fibroblast activation protein inhibitor) in the aqueous core ( D PPA-TRPP/Tab). 112 Additionally, DOX conjugation within the chain served as both an ICD inducer and a hydrophobic component. D PPA-TRPP/ Tab reassembled into a micellar structure in vivo with drug release in the weakly acidic TME.…”

“…Normally, the high levels of ROS, abundant cancer-associated fibroblasts (CAFs) in the TME, and immune checkpoints enable immunosurveillance of tumors. A novel tumor TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was developed by Yang et al with conjugating the D-peptide antagonist ( D PPA-1) of programmed death ligand-1 onto the surface and encapsulating talabostat mesylate (Tab), a fibroblast activation protein inhibitor) in the aqueous core ( D PPA-TRPP/Tab) . Additionally, DOX conjugation within the chain served as both an ICD inducer and a hydrophobic component.…”