Lysosomal Disruption Elicits Immunogenic Cell Death: A Saponin-Nanoaluminum Adjuvant for Enhanced Cancer Immunotherapy.

Abstract

Inducing lysosomal membrane permeabilization (LMP) represents an alternative therapeutic strategy that bypasses conventional genetic or protein targets and triggers cell death by physically tumor disrupting. Herein, QS-21, an FDA-approved saponin with membrane-disruptive capability was loaded onto an aluminum-based adjuvant (denoted as QS-NanoAlum) to induce LMP effects and trigger tumor immunogenic cell death (ICD) through a "self-lysis" mechanism. Leveraging its positive surface charge, intratumorally administered QS-NanoAlum could be easily adhered to tumor cell membranes, facilitating efficient cellular internalization. Within the acidic lysosomal environment, QS-NanoAlum underwent degradation and subsequently released QS-21, leading to LMP effect and the cytosolic leakage of hydrolytic enzymes. The released hydrolases and QS-21 would further inflict collateral damage to cellular structures and organelles, including the plasma membrane, nucleus, mitochondria, and endoplasmic reticulum, which ultimately culminated in ICD. Notably, excess QS-NanoAlum could efficiently adsorb the released tumor-associated protein antigens (TAAs) during ICD, forming an antigen depot at the injection site that sustained long-term immune stimulation. Our in vivo studies also demonstrated that QS-NanoAlum significantly suppressed tumor growth and enhanced immune cell infiltration into tumor tissues. Finally, this strategy that physically disrupting the cellular "recycling center" to provoke cell disintegration and elicit robust ICD, offering a promising paradigm for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Conventional cancer therapies target specific mutations but are limited by tumor heterogeneity and resistance. We introduce a new paradigm that physically disrupts tumor cells via lysosomal membrane permeabilization (LMP), bypassing molecular targets. Our system, QS-NanoAlum (QS-21 loaded to an aluminum adjuvant), triggers immunogenic cell death through a "self-lysis" mechanism. Positively charged QS-NanoAlum is internalized and degrades in acidic lysosomes, releasing QS-21 to induce LMP. Released hydrolases cause widespread organelle damage, leading to robust immunogenic cell death. Excess QS-NanoAlum adsorbs tumor-associated antigens, forming a sustained immune depot. In vivo, QS-NanoAlum suppresses tumor growth and enhances immune infiltration, validating its potential for cancer immunotherapy.