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Novel Taxol-Derivative, STO-1, Induces Selective Anti-Tumor Immunity and Sustained Remission of Glioblastoma Without Triggering Autoimmune Reactions

Shubhasmita Mohapatra,Adrian Guerrero,Neha Rahman,Khondoker Takia Zaman,Jing Wu,Callistus Onyeagba,Chanyue Hu,M. Pellegrini,Jayaram Vankudoth,Seiya Kitamura,Lauren O'Donnell,Y. Wadghiri,Probal Banerjee

Published 2025 in Cells

ABSTRACT

Highlights We have created a novel Taxol derivative that induces anti-tumor immunity in glioblastoma (GBM) tumors without triggering autoimmune reactions, leading to long-term remission in a syngeneic mouse model of GBM.➢ Creating anti-tumor immunity to treat cancers has been gaining ground but this approach also involves the risk of triggering systemic inflammation and autoimmunity.➢ Using a calculated strategy, we have created a novel Taxol derivative, STO-1, that induces anti-tumor immunity within glioblastoma (GBM) tumors.➢ Most notably, STO-1 does not trigger systemic inflammation and autoimmune reactions.➢ As an immunotherapeutic, STO-1 accomplishes sustained remission in a syngeneic mouse model of GBM. Abstract Reprogramming of macrophages into the inflammatory state (also known as M1) is currently considered as an effective way of eliminating cancer cells, but systemic deployment of this strategy is likely to induce dangerous autoimmune reactions. Consequently, converting immunosuppressive M2-type macrophages into M1 systemically is not a safe and effective therapeutic approach against cancer. Through cleavable covalent linking of curcumin to the chemotherapeutic agent Paclitaxel (Taxol), we have created a novel prodrug (STO-1) that, upon intravenous delivery, selectively reprograms tumor-associated microglia and macrophages (TAMs) and eliminates glioblastoma (GBM) without triggering autoimmunity. Demonstrating its therapeutic efficacy, prolonged treatment of six orthotopic GBM-bearing mice with STO-1 resulted in 67% long-term survival, with three surviving mice exhibiting complete tumor clearance and one displaying minimal residual disease, as confirmed by high-resolution ex vivo T2-weighted MRI 85 days after tumor inoculation. In contrast, the vehicle-treated mice displayed extensive intracranial tumors with edema and hemorrhage. Mechanistically, scRNA-seq analysis indicated induction of multiple M1-associated transcripts (ccrl2, cxcl9, ccr2, ccl5) consistent with robust TAMs reprogramming. In striking contrast to the M2⟶M1 reprogramming of TAMs, M1-type macrophages were suppressed in the spleens of STO-1-treated cancer-free mice. Therefore, STO-1 induces selective anti-tumor immunity and GBM elimination without triggering systemic autoimmune reactions.

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