**6. GAGs as Potential Cancer Therapy Response Biomarkers**

The physical barrier represented by HA in the TME restricts immune therapy efficacy by hindering antibody and immune cell access. It was shown in 50% of HER2(3+) primary breast tumors and almost 50% of EGFR(+) head and neck squamous cell carcinomas that the tumor tissue characterized by high HA expression is associated with immune therapy resistance. The matrix containing high HA deposition hinders NK immune cell access to tumor cells. The depletion of HA by PEGPH20 (pegylated recombinant human PH20 hyaluronidase) propagates NK cells' access to these tumors. In vitro, the same mechanisms enhanced trastuzumab- or cetuximab-dependent antibody-dependent cellular toxicity (ADCC), while the in vivo experiments also demonstrated treatment efficacy. Considering that the tumor HA deposition can be used as a marker for immune therapy resistance, other clinical management protocols can be developed [271].

In colorectal cancer, it was established that glycosylation alters over 80% of human proteins and that aberrant glycosylation is involved in cancer development and progression. Glycan changes (e.g.,carbohydrate antigen CA 19-9 or carcinoembryonic antigen) are already established biomarkers in this cancer. Recent reports have shown that altered glycosylations can be involved in drug resistance mechanisms and indicate new predictive biomarkers [272].

GAGs are utilized as biomarkers in other disease types, including mucopolysaccharidoses (MPSs) [273]. The MPSs present approximately 30% of lysosomal storage diseases and are induced by inefficient GAG breakdown due to active enzyme deficiencies [274]. Without treatment options, patients exhibiting severe MPS forms die within the first two decades of life [273].
