Letter to the Editor: Lysosomal vulnerability as a therapeutic axis for overcoming proteasome inhibitor resistance in gastric cancer

Abstract

Proteasome inhibitors such as bortezomib have shown limited efficacy in solid tumors, largely due to intrinsic and acquired mechanisms of drug resistance. In the recent issue of the World Journal of Gastroenterology, Li et al demonstrated that a wogonin derivative markedly enhances the antitumor activity of bortezomib in gastric carcinoma by disrupting lysosome-mediated drug sequestration. This work provides important mechanistic insights into how lysosomal function contributes to therapeutic resistance and highlights lysosomal vulnerability as a potential target for combination strategies. Lysosomes are dynamic regulators of cellular stress responses and drug tolerance, not merely degradative organelles. Activation of transcription factor EB-dependent lysosomal biogenesis represents a key adaptive mechanism enabling cancer cells to buffer proteotoxic stress. The findings reported by Li et al support this conceptual framework by demonstrating that interference with lysosomal integrity can restore proteasome accessibility and enhance cytotoxic efficacy. Notably, validation in patient-derived organoids strengthens the translational relevance of targeting lysosomal pathways. This approach may help identify responsive subsets and optimize regimens. Future studies are warranted to further elucidate lysosome-dependent resistance mechanisms and to explore the safety and therapeutic integration of lysosome-disrupting strategies. Collectively, these insights underscore lysosomal vulnerability as an emerging therapeutic axis for overcoming proteasome inhibitor resistance in gastric cancer.

Keywords: Lysosomal vulnerability; Proteasome inhibitor resistance; Bortezomib; Gastric cancer; Transcription factor EB; Patient-derived organoids

Core Tip: Proteasome inhibitor resistance in solid tumors remains a major therapeutic challenge. This letter highlights lysosomal vulnerability as a central adaptive mechanism underlying bortezomib resistance in gastric cancer. By reframing lysosomes as active regulators of proteotoxic stress and drug sequestration rather than passive degradative organelles, the discussed study supports lysosome-targeted strategies as a promising therapeutic axis. Patient-derived organoid validation further underscores the translational relevance of intercepting lysosome-centered stress adaptation to enhance proteasome inhibitor efficacy.