Cancer cell-dependent increase in senescence-like populations following exosome treatment: The role of extracellular matrix and cellular glycocalyx

Abstract

We read with the great interest the study by Ababneh et al in which induced mesenchymal stem cell-derived exosomes were shown to exhibit a stronger and more sustained anti-proliferative effect by inducing a senescence-like state without apoptosis. The results obtained by the authors highlight the features of the effects of senescent drift induction in surrounding tissues. In the light of these findings, the role of the properties of extracellular matrix and cellular glycocalyx in responses of human tumors to therapy remain uninvestigated. These extracellular barriers appear to be significant obstacles to effective cancer therapy, especially in relation to the use of unique properties of tumor microenvironment for the immunotherapy-resistant cancer treatment.

Key Words: Cancer; Extracellular matrix; Glycocalyx; Exosomes; Extracellular vesicles; Tumor microenvironment

Core Tip: Extracellular vesicles can promote or inhibit oncogenic progression by shaping the tumor microenvironment. The efficiency of extracellular vesicle delivery can be affected by the extracellular matrix and altered glycocalyx. The tumor extracellular matrix and cellular glycocalyx can create a permissive niche for invasion, immune evasion, and metastasis. These factors are also essential for predicting the effectiveness of targeted therapies and the responses of bystander cells. Understanding these factors is crucial for treating cancers that are resistant to immunotherapies.

TO THE EDITOR

We read with special interest the study by Ababneh et al[1] in 2025, in which it was found that induced pluripotent stem cell-derived mesenchymal stem cell-derived exosomes exhibited a stronger anti-proliferative effect by inducing a senescence-like state without apoptosis. We would like to discuss an interesting phenomenon related to the differential effects of various cell cultures to exosomes derived from different sources. To explain this phenomenon, the approach of ‘senescent drift’ was determined to explain the targeted transfer of senescence-associated secretion phenotype (SASP)-associated exosomes, depending on tissue properties[2]. However, the underlying cause of this phenomenon and possible use-cases of them remains unclear.

TISSUE-SPECIFIC OBSTACLE OF EXTRACELLULAR FACTORS

The therapeutic mechanisms of cancer cell death are characterized by the exposure of damage-associated molecular patterns. These patterns are recognized by innate immune cells, which can then prime cell responses[3]. The effectiveness of targeted therapy depends on various factors related to molecular and cellular mechanisms and spatial-like patterns. For example, intratumor injection of therapeutics or exosomes is a more effective way for cancer treatment to be delivered than systemic delivery, which is related to the mechanical overcoming of the first physical barrier line in tumors[3,4]. It is well-known that the unique mechanical properties of the tumor extracellular matrix (ECM) differ from normal conditions and may hinder delivery of therapeutics both for tumor and bystander cells[5,6], as well as affect antigen presentation and subsequent T-cell activation[7]. In light of the promising principles of cancer immunotherapy, bystander cell reactions can be considered intermediate players in immune responses. This could explain why some drugs are effective even without targeted delivery mechanisms[8]. Recent studies have shown that alterations to the glycocalyx affect dendritic cells and prevent the development of therapeutic mechanisms. These alterations also affect the tumor cell ECM, which is composed of macromolecules and glycocalyx properties[9,10]. The phenomenon of targeting the tumor ECM and cellular glycocalyx should be recognized as an emerging frontier in cancer therapy. This unconventional feature should be considered to avoid misunderstanding the basic principles of targeted anti-cancer therapeutics, including monoclonal antibody conjugates and mRNA vaccines.

The SASP phenotype refers to the way senescent cells actively modify their environment by secreting various soluble factors and extracellular vesicles, i.e., senescent ‘poisoning’ of the extracellular environment. In contrast, senescent drift refers to the long-term spread or systemic integration of a senescence-like state in tissue caused by tissue-specific interactions. Figure 1 explains the differences between the SASP and senescent drift, and the ECM/glycocalyx-dependent transfer of the extracellular vesicles.

Figure 1 Explanation of the differences between the senescence-associated secretion phenotype and senescent drift, and the extracellular matrix/glycocalyx-dependent transfer of the extracellular vesicles. Created with Biorender.com.

Tissue-specific ECM barrier functions can facilitate the design of drugs that effectively transport through target tissues, thereby improving their therapeutic efficacy[11,12]. Heparan sulfate proteoglycans function as receptors on the cell surface, with their heparan sulfate chains binding to exosomes, often due to the polyanionic nature of the heparan sulfate chains. This binding could trigger the internalization of the exosome into the target cell. Therefore, the glycocalyx imposes biophysical barriers that are also linked to inhibitory receptor signaling pathways in immune cells, which are related to cell reception and endocytosis[9,13-15].

The properties of tumor ECM and the cellular glycocalyx could regulate the effectiveness of targeted therapy through altered cellular endocytosis, as well as the responses of bystander cells. These bystander effects may include altered cytokine secretion, ECM remodeling, or immune cell infiltration modulation, all of which can impact treatment outcomes. Understanding and potentially manipulating the tumor ECM and glycocalyx’s biophysical and biochemical features are crucial for improving the precision and efficacy of targeted cancer therapies through modification of the structural biomolecules composition and organization.

CONCLUSION

The tumor ECM and cellular glycocalyx are key players in predicting the effectiveness of exosome-based targeted therapy, as well the responses of bystander cells. These two extracellular factors remain the final frontier in treating immunotherapy-resistant cancers. Future studies should focus on understanding the interactions between drugs and extracellular barriers in order to develop targeted delivery systems or combination therapies that can improve the effectiveness of immunotherapy in treating resistant cancers.