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Published on: March 6, 2018
Spatiotemporally Controlled Lysosomal Membrane Permeabilization Amplifies STING-Driven Antitumor Immunity in Prostate
Qishu Jiao1, Jiaqi Zhang1, Chunlu Wang2
1Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Abstract:
Prostate cancer (PCa) remains a major clinical challenge due to therapeutic resistance and immunologically cold tumor microenvironment. Lysosomal membrane permeabilization (LMP)-induced lysosome-dependent cell death offers an alternative route to eliminate resistant tumor cells and initiate immunogenic cell death, yet its efficacy is often limited by insufficient spatiotemporal control and immune activation. Here, we report a spatiotemporally programmable supramolecular nanoplatform (Cu-P-MSA) that integrates lysosome-targeted sonodynamic therapy with tumor-confined innate immune activation for PCa treatment. Cu-P-MSA is a modular self-assembling peptide incorporating a PSMA-targeting ligand, morpholine moiety, and cathepsin B-cleavable linker, enabling tumor-selective uptake and in situ formation of fibrous sonosensitizer depots within lysosomes. Upon ultrasound irradiation, a glutathione-responsive open-shell sonosensitizer induces controlled LMP, simultaneously activating ferroptosis and pyroptosis and promoting immunogenic cell death. Meanwhile, tumor-specific release of a STING agonist MSA-2 elicits robust type I interferon responses, driving dendritic cell maturation and cytotoxic T-cell infiltration. This coordinated lysosomal disruption-immune amplification strategy effectively reprograms the tumor immune microenvironment and suppresses both primary and distant tumors, with inhibition rates reaching 84.3% and 77.5%, respectively. Overall, this work establishes a spatiotemporally controlled supramolecular approach that integrates lysosomal disruption with innate immune activation to overcome therapeutic resistance and immunosuppression in PCa.
Insights
This study introduces a novel nanoplatform for prostate cancer (PCa) treatment. It combines ultrasound-triggered lysosomal disruption with immune activation to overcome therapy resistance and suppress tumor growth.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Prostate cancer (PCa) presents significant challenges due to treatment resistance and an immunosuppressive tumor microenvironment.
- Lysosomal membrane permeabilization (LMP)-induced cell death offers a potential strategy against resistant PCa but lacks precise control and immune stimulation.
- Current therapies struggle to overcome both tumor resistance and immune evasion in PCa.
Purpose of the Study:
- To develop a spatiotemporally programmable supramolecular nanoplatform for enhanced prostate cancer treatment.
- To integrate lysosome-targeted sonodynamic therapy with tumor-confined innate immune activation.
- To overcome therapeutic resistance and immunosuppression in the PCa tumor microenvironment.
Main Methods:
- A modular self-assembling peptide nanoplatform (Cu-P-MSA) was designed, incorporating a PSMA-targeting ligand, morpholine moiety, and cathepsin B-cleavable linker.
- Cu-P-MSA self-assembles into fibrous depots within lysosomes for tumor-selective uptake and in situ sonosensitizer formation.
- Ultrasound irradiation triggered controlled LMP, activating ferroptosis and pyroptosis, while releasing a STING agonist (MSA-2) to stimulate innate immunity.
Main Results:
- The nanoplatform demonstrated tumor-selective uptake and efficient lysosomal disruption upon ultrasound activation.
- Controlled LMP induced immunogenic cell death, activating ferroptosis and pyroptosis pathways.
- Tumor-confined release of the STING agonist promoted type I interferon responses, dendritic cell maturation, and cytotoxic T-cell infiltration.
- Significant suppression of both primary (84.3%) and distant (77.5%) tumors was observed, indicating effective immune reprogramming.
Conclusions:
- The developed supramolecular nanoplatform effectively integrates lysosomal disruption with innate immune activation for prostate cancer therapy.
- This coordinated strategy overcomes therapeutic resistance and immunosuppression by reprogramming the tumor microenvironment.
- The study establishes a promising spatiotemporally controlled approach for treating challenging cancers like PCa.
