*5.2. Heparan Sulfate-Based Therapeutic Opportunities*

Based on promising preclinical data, some HS-based therapies are currently under clinical investigation although none was yet approved [212–214]. Difficulties in interpreting data with HS mimetics are mainly due to their pleiotropic effects [160,206,207].

Currently, leukocyte-based anticancer therapies like Chimeric Antigen Receptor-T (CAR-T) cell therapy, dendritic cell vaccines and viral-therapeutic delivery exploiting HPSE are being developed [102,215]. HPSE is able to change the function of HSPGs in the tumour microenvironment and is a regulator of several cancer hallmarks [216], namely, angiogenesis and the development of metastasis [105,217]. So, targeting HPSE and modulating its activity is a very valuable strategy to overcome several cancer features and improve disease outcome [102,218].

Another possible opportunity for intervention could be the use of the endostatin domain of collagen XVIII. Endostatin exerts an efficient inhibitory effect on tumour angiogenesis and growth [219,220]. Gastric cancer patients with subsequent liver metastasis are extensively studied, and several phase II clinical trials are using recombinant endostatin (either alone or combined with other drugs) as an anti-tumour agent [221–223]. In addition, the effect of endostatin in advanced well-differentiated pancreatic neuroendocrine tumours is being tested [224].

Synthetic peptides that interfere with the interaction between HS and its binding partners, also represent an appealing alternative [225]. This approach allows a specific blocking of interaction with the growth factors, acting on particular pathways. Furthermore, a large number of small molecules can also regulate glycosylation by modulating glycosyltransferases and glycosidases activity [218,226] and are emerging as new therapeutic strategies [226–228].

Recently, another class of enzymes have been capturing attention: the 3-*O*-sulfotransferases (3OSTs). These enzymes produce a rare HS modification, glucosaminyl-3-*O* sulfation, which affects the selective binding of several ligands. Interestingly, these enzymes can either act as pro or anti-tumourigenic according to the cellular specific context [229,230]. An important challenge in this field is to determine how the HS glycan sequence and sulfation pattern drive ligand binding specificity.

Furthermore, the development of specific HSPG targeted therapeutic approaches is also being studied. Antibody-targeting of SDC1 has been used alone or combined with chemotherapy to treat multiple myeloma [231], and a clinical trial using CAR-T cells recognising SDC1 suggests that the treatment is safe, well-tolerable and has potential antitumour activity [232]. In the same line, in hepatocellular carcinoma, the strategies of immunotoxin and CAR-T cells against GPC3 are showing promising results and are under clinical trials [233–235].
