Inhibition of chemokine CXCL12 modulates the tumor microenvironment in glioblastoma and potentiates immune checkpoint inhibitor efficacy in a tissue-specific manner

Background: Immunotherapy, while effective for many extra-cranial solid tumors, has not shown benefits against glioblastoma. Limited T cell infiltration and an immunosuppressive tumor microenvironment (TME) are among the main barriers to successful immunotherapy. We hypothesized that blocking the chemokine CXCL12 would modulate the TME composition and reverse GBM resistance to immunotherapy. Methods: We used a syngeneic murine SB28 GBM model resistant to immune checkpoint inhibitor (ICI) and compared orthotopic and subcutaneous tumors to differentiate tumor-intrinsic factors from CNS-related barriers. We treated SB28 tumor-bearing mice with vehicle, ICI, CXCL12 inhibitor (NOX-A12), or a combination of NOX-A12 with ICI. We assessed treatment effects on immune cell populations in the blood and the TME, and on tumor growth and mouse survival. Results: tumor-associated macrophages (TAM) and slowed tumor growth. However, in orthotopic tumors, TAM populations remained unaffected, and survival was not extended, despite similar T-cell modulation, supporting the role of TAM in mediating GBM resistance to ICI. Conclusion: CXCL12 inhibition demonstrates therapeutic potential in facilitating anti-tumor immune response by dual mechanism, including T cell expansion and TAM reduction. The inability to deplete TAMs and improve survival in intracranial GBM underscores the need to address brain-specific mechanisms underlying TAM persistence to advance immunotherapy in GBM.