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.

Key Words: 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.

TO THE EDITOR

We read with great interest the recent article by Li et al[1], published in the recent issue of the World Journal of Gastroenterology, which demonstrated that a wogonin derivative significantly enhances the antitumor efficacy of bortezomib in gastric carcinoma by disrupting lysosome-mediated drug sequestration. By elucidating a previously underrecognized mechanism of proteasome inhibitor resistance[2], this study provides important mechanistic insights and highlights lysosomal vulnerability as a potential therapeutic target in solid tumors[3].

Proteasome inhibitors such as bortezomib have achieved remarkable success in hematological malignancies; however, their clinical efficacy in solid tumors remains limited[4]. Increasing evidence suggests this discrepancy arises not merely from inadequate target engagement, but rather from cancer cells' ability to adapt to proteotoxic stress via coordinated organelle-based defense mechanisms[5]. In this context, lysosomes act not as passive degradative compartments, but as dynamic regulators of cellular stress responses, metabolic adaptation, and drug tolerance[2,6]. Activation of transcription factor EB-dependent lysosomal biogenesis represents a central adaptive mechanism by which tumor cells enhance lysosomal capacity. This process buffers proteotoxic stress caused by proteasome inhibition and sequesters cytotoxic agents away from their intended targets[7]. This lysosome-centered adaptive response may represent a common stress-buffering strategy among various solid tumor types, potentially explaining the generally limited efficacy of proteasome inhibitors beyond hematological cancers. However, tumor cell reliance on lysosome-mediated stress buffering likely varies according to tumor type, genetic background, and microenvironmental context, emphasizing the need for tumor-specific validation of lysosome-targeted therapies.

LYSOSOMAL VULNERABILITY AND PROTEASOME INHIBITOR RESISTANCE

The work by Li et al[1] provides compelling experimental evidence supporting this conceptual framework. Their findings demonstrate that bortezomib exposure promotes lysosomal expansion and drug sequestration, thus reducing proteasome accessibility and therapeutic efficacy[8,9]. Importantly, disruption of lysosomal integrity by wogonin derivative effectively reverses this adaptive response, restoring proteasome engagement and enhancing cytotoxic stress. By positioning lysosomal function upstream of proteasome inhibitor resistance, this study reframes lysosomes as critical regulatory hubs rather than downstream effects of drug-induced stress[10]. From an editorial perspective, this reframing is particularly significant, shifting therapeutic attention from solely enhancing proteasome inhibition toward targeting upstream organelle-based resistance mechanisms.

Such a perspective extends beyond the specific compounds investigated and suggests that lysosomal vulnerability may constitute a broadly applicable therapeutic axis in the treatment of solid tumors[3,11].

TRANSLATIONAL IMPLICATIONS AND FUTURE DIRECTIONS

A notable strength of the study is the validation of these mechanistic insights in patient-derived organoid models. Organoids preserve essential features of tumor architecture, genetic heterogeneity, and stress-response capacity, thereby providing a translationally relevant platform for therapeutic evaluation[12]. The finding that lysosome-disrupting strategies enhance the efficacy of bortezomib in patient-derived gastric cancer organoids effectively bridges experimental observations with potential clinical application. In this context, organoid-based systems may be particularly valuable for capturing lysosome-dependent stress adaptations that are often diminished or absent in conventional two-dimensional cell culture models[13].

This approach may enable the identification of patient subsets most likely to benefit from lysosome-targeted combination therapies[14] and supports the integration of organoid-based platforms into precision oncology workflows[15].

These findings also raise several important questions for future investigation. Further studies are needed to define the molecular determinants governing lysosome-dependent drug sequestration across diverse tumor contexts and to establish the therapeutic window and selectivity of lysosome-disrupting strategies. Given the essential role of lysosomes in normal cellular homeostasis, careful assessment of on-target and off-target effects will be critical to minimize potential toxicity in non-malignant tissues[16]. It will also be important to determine whether targeting lysosomal vulnerability can be safely combined with other treatment modalities, including targeted therapies and immunotherapies, and whether biomarkers of lysosomal activity or transcription factor EB signaling can guide patient stratification[17]. Addressing these issues is essential for translating lysosomal vulnerability from a compelling mechanistic concept into a clinically actionable therapeutic strategy.

CONCLUSION

In summary, the study by Li et al[1] highlights lysosomal vulnerability as an emerging, mechanistically grounded therapeutic axis for overcoming proteasome inhibitor resistance in gastric cancer. By redefining lysosomes as active mediators of drug tolerance and stress adaptation, this work opens new avenues for combination strategies aimed at enhancing the efficacy of proteasome inhibition in solid tumors.