热敏透明质酸-锰-辣椒素复合纳米凝胶通过调节肿瘤微环境改善 NKG(2)D/CAR-T 黑色素瘤治疗

Intratumorally injection of CAR-T cells to treat melanoma can reduce the incidence of systemic side effects and ensure an adequate concentration of CAR-T cells.

However, few targeting ligands and hostile tumor microenvironment (TME) inhibit the CAR-T cells' survival and infiltration. An in situ hyaluronic acid manganese-capsaicin complex nanogel (HA-Mn-CAP Gel) was designed by forming complex nanogel based on the main skeleton material of hyaluronic acid (HA). It targeted CD44 and TRPV 1 receptors through HA and CAP, concentrated and released Mn at melanoma, subsequently relieving the hypoxia in the tumor and increasing the expression of CAR-T cells' specific ligands.

Cell experiments showed that HA-Mn-CAP Gel significantly enhanced the expression of representative NKG 2 D ligands (MICA/B and ULBP 2/5/6 ) >2. 7 times on A375 melanoma cells. Sequential administration of HA-Mn-CAP Gel and NKG 2 D/CAR-T increased the tumor inhibition rate about 1.

5 times that of the NKG 2 D/CAR-T group in melanoma-bearing NSG mice. The results of immunohistochemistry and immunofluorescence assays showed that the combined HA-Mn-CAP Gel and NKG 2 D/CAR-T significantly increased the proliferation and infiltration of T cells, especially for CD8 + cells.

Therefore, the new promising strategy of increasing the target ligand expression and adjusting TME before administering CAR-T cells is suitable for treating solid tumors.