Breast Cancer (BCa), a complicated heterogeneous disease, is the most frequent malignancy in females, and it is the leading cancer-related mortality worldwide [1]. Generally, BCa is categorized into three different types based on the presence or absence of molecular biomarkers for (1) estrogen or (2) progesterone receptors and (3) human epidermal growth factor 2 (ERBB2; formerly HER2) [2]. These molecular biomarkers are hormone receptor positive/ERBB2 negative (HR+/ERBB2-; 70% of patients), ERBB2 positive (ERBB2+; 15%-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%) [2,3]. The preferable clinical treatment methods for BCa comprise chemotherapy, radiotherapy, surgery, endocrine and/or targeted therapies [4]. However, approx. 70-80% of the patients with early-stage, non-metastatic BCa can be cured with current treatment approaches [5] whereas, some patients with certain BCa subtypes, particularly with triple-negative BC (TNBCa), still face an inevitable progression and even leads to poor prognosis [6].

Chemoresistance, which is the capacity of cancer cells to resist chemotherapeutic drugs, leading to disease relapse and metastases [7], is believed to be a key factor of the failure of anti-BCa chemotherapy. The better understanding of the chemoresistance mechanisms will be urgently required to improve the therapeutic treatments to circumvent the issue of chemoresistance. Although attempts have been made to restore sensitivity to existing chemotherapeutic drugs and overcome drug resistance in BCa, the effects remains disappointing, as some BCa patients may experience relapse after long-termed chemotherapeutic treatments [8]. The chemoresistance mechanisms in BCa, unless otherwise stated, could be classified into several branches, such as: (1) cell membrane influences drug absorption [8-10], (2) transport and efflux [11,12]; (3) membrane glycoproteins functioning as efflux pumps [13-15]; (4) enzymatic inactivation of antitumor drugs through altered metabolism [16,17]; (5) DNA repair mechanisms [18-20]; (6) and the tumor microenvironment [21,22].

Lysosomes, an essential component of the inner membrane system, are considered the ‘‘garbage disposal’’ of cells because they contain more than 60 different types of hydrolases (proteases, nucleases, lipases, etc.,), which degrade various biological polymers, including nucleic acids, carbohydrates, lipids, and misfolded proteins [23]. Lysosomes mature from endosomes, move along the cytoskeleton, and undergo fusion and fission processes, as well as transient kiss-and-run contacts with other membrane-bound organelles [24]. Intracellular materials are transported to lysosomes through autophagy, whereas exogenous materials can be engulfed from outside the cell via endocytosis or phagocytosis, and delivered to lysosomes, which are the final organelle where endocytosed materials are degraded [25]. Lysosome-degraded materials, also known as building blocks, can be recycled and reused by cells to build up various macromolecules required for cell proliferation, differentiation and survival [25,26]. Unlike proteasomal degradation of ubiquitinated proteins, autophagy is the major degradation pathway for intracellular proteins, and more importantly, it can accommodate organelles and cytoskeletal components. Therefore, it is not surprising that lysosomes serve as a crucial driver of various cellular processes related to signaling transduction [27-29], metabolism [30-33], lipid homeostasis, intracellular transport [34-39] and remodeling of the extracellular matrix (ECM) [40].

In cancer cells, metabolic processes are reprogrammed, leading to an increase in metabolic activity due to the cells’ heightened demand for nutrients [41]. This metabolic shift supports rapid growth and proliferation [41]. To meet these energy and nutrient demands, lysosomal and autophagy activities are also upregulated [42]. As mentioned above, lysosomes play a crucial role in degrading and recycling cellular components, while autophagy facilitates the breakdown of organelles and proteins into their basic monomers, such as amino acids and lipids [43]. These recycled materials are then used to fuel biosynthesis and energy production, further promoting cancer cell survival [43]. Autophagy not only enables cancer cells to withstand metabolic stress but also helps them survive under conditions like chemotherapy [44]. Research has shown that inhibiting autophagy can restore chemotherapy sensitivity, suggesting that autophagy is a critical mechanism by which cancer cells resist therapeutic interventions [44]. The lysosomes, as a key player in these processes, are central to cancer cell survival and drug resistance.

Recent studies have revealed an additional role of lysosomes in chemotherapy resistance: the ability to sequester chemotherapy drugs [45]. This can occur either through passive diffusion or active transport by P-glycoprotein, a membrane-associated efflux pump that is frequently overexpressed in cancer cells [46]. P-glycoprotein typically functions by pumping drugs out of the cell, but when localized to the lysosomal membrane, it transports chemotherapy drugs into the lysosomes [47]. By trapping these drugs within lysosomes, the concentration of chemotherapy agents in the cytoplasm is reduced, weakening their intended therapeutic effects on the cancer cells [42]. This sequestration mechanism is a significant challenge in cancer treatment, as it contributes to multidrug resistance, a major obstacle in the effective eradication of tumors [42]. Targeting lysosomal P-glycoprotein activity or preventing drug sequestration in lysosomes could therefore represent promising strategies for overcoming drug resistance in cancer therapy [48].

Chemoresistance in BCa is still an unsolvable problem. Increasing evidence suggests that lysosomes might be a crucial driver of chemoresistance in BCa; however, our current understanding of how lysosomes contribute to chemoresistance in BCa is poorly understood. Through computational and systems biology approaches, Aref et al., screened a total of 435 genes involved in the biogenesis and functional structure of lysosomes, and subsequently identified top six lysosomal genes (PRF1, TLR9, CLTC, GJA1, AP3B1 and RPTOR) critical for lysosomal structure and function. These genes may serve as potential therapeutic targets for overcoming chemoresistance in BCa [49]; however, further investigations are needed.

Furthermore, Anne et al., showed that inhibition of cyclin D–CDK4/6 kinase might also represent an attractive therapeutic strategy for BCa treatment [45]. Indeed, it was demonstrated that mice lacking cyclin D1, or CDK4 are completely resistant to the development of BCa driven by HER2 oncogene, and a subset of TNBCs critically requires CDK4 and CDK6 for their proliferation. Nevertheless, these TNBCs are resistant to CDK4/6 inhibition as CDK4/6 inhibitors such as palbociclib and other currently available CDK4/6 inhibitors become sequestered into tumor cell lysosomes [45]. This sequestration is caused by enhanced lysosomal biogenesis and increased numbers in TNBC cells [45].

Additionally, Chunhong et al., has illuminated that the lysosomal cation channel, transient receptor potential mucolipin 1 (TRPML1), abundantly expresses in BCa cells and exhibits high sensitivity to salinomycin, a drug used to selectively kill cancer stem cells (CSCs) [50]. Intriguingly, pharmacological inhibition and genetic depletion of TRPML1 remarkably surged ferroptosis in breast CSCs, diminished their stemness, strengthened the sensitivity of BCa cells to chemotherapeutic drug doxorubicin, and significantly alleviating tumor formation and growth in mouse xenograft model [50]. These findings suggest that selectively targeting TRPML1 to eliminate CSCs might be a promising strategy for BCa treatment [50].

It is evident that lysosomes play a multi-directional role in the development and progression of malignant tumors. Most chemotherapeutics exerted in the clinic are lipophilic, which is weak-based drugs readily sequestered in the acidic lysosomal lumen. Once in the lysosomal lumen, these compounds are rapidly protonated and trapped in these organelles, thereby abolishing their cytotoxic effect [51]. Lysosomes control the degradation of cellular constituents and organelles after their fusion with autophagosomes, and disturbance of lysosomal pathways causes malfunctioning of autophagic processes, which promotes cancer progression and chemoresistance [24]. In addition, induction of autophagy during cancer therapy, in combination with lysosomal proteolysis are thought to be a major factor of immunosurveillance and resistance to immunotherapy [52]. Therefore, it is widely accepted that lysosomes are one of central players enabling cancer cells to evade chemotherapeutic effects; however, our current understanding of how lysosomes promote the establishment of chemoresistance mechanisms towards BCa progression is limited. As mentioned above, Aref et al., identified several lyososmal genes regulating lysosomal structure, function and biogenesis in BCa cells; however, their role(s) in regulating chemosistance mechanisms has not been explored. In other words, TRPML1, a Ca²⁺-releasing cation channel that keeps an important role in regulating the Ca²⁺ signaling and homeostasis, is located on lysosomal membranes, and this channel is believed to be intracellular storage for several essential trace ions including Ca²⁺, Zn²⁺ and Fe³⁺ [53], contributing to the regulation of many cellular events. Specifically, the TRPML1-mediated release of Zn²⁺ from lysosomes causes mitochondrial dysfunction and necrotic cell death in metastatic melanoma cells. In contrast, the TRPML1-mediated release of Ca²⁺ is a key signaling mechanism that regulates various lysosome-related functions comprising lysosomal trafficking, autophagy, and interactions with other organelles within the cells [54]. Meanwhile, iron predominantly exists in its unreactive Fe³⁺ inside the shell of ferritin, and degradation of ferritin in lysosomes releases iron in the form of Fe²⁺, catalyzing the lipid peroxidation to an excessive extent and triggering ferroptotic cell death [55]. As CSCs require a higher demand for iron metabolism than non-CSC cells; blocking iron ion transporter would be a promising cancer therapy to target and kill CSCs [56].

It is obvious that lysosomal membrane proteins and lysosomal enzymes play an important role in the development and progression of malignant tumors; therefore, monitoring and determining the functional effects of lysosomes could facilitate the establishment of precise personalized treatment methods. Lysosomal sequestration is one of the most noticeable mechanisms that enables cancer cells to resist of chemotherapeutic drug’s cytotoxic effects. Drugs include, but not limited to anthracyclines, mitozantrone, platinum cytostatics, and some tyrosine kinase inhibitors. Lysosomal-mediated drug resistance indicate that lysosomes serve as one of crucial drivers of chemoresistance in cancer progression. Unfortunately, our current understanding of how lysosomes regulate chemoresistance in BCa is limited. Consequently, additional studies will be required to focus on this aspect.

None declared.

We received no funding for the writing of this paper.