Covalent tumor anchoring spatially orchestrates antitumor immunity

Area of Science:

• Oncology
• Immunology
• Biotechnology
• Protein Engineering

Background:

• Protein immunotherapies show promise for tumor rejection but suffer from limited spatial control due to reversible target engagement and systemic leakage.
• Current methods often lead to off-target effects and systemic immunopathology, necessitating improved strategies for localized and sustained therapeutic action.

Purpose of the Study:

• To develop a novel platform of covalently anchored tumor immunotherapeutic proteins (CATIPs) for enhanced spatial control and efficacy.
• To evaluate the therapeutic potential of CATIPs in preclinical models, assessing their ability to induce durable, tumor-specific antitumor immunity while minimizing systemic toxicity.

Main Methods:

• Development of a modular CATIP platform utilizing proximity-enabled covalent chemistry to immobilize immune cues on tumor cell surfaces.
• CATIPs were engineered with tumor-targeting nanobodies and payloads for T cell engagement, co-stimulation, and cytokine support.
• Preclinical evaluation in human PBMC-reconstituted NSG mice with EGFR-positive tumors and immunocompetent melanoma models.

Main Results:

• CATIPs completely eradicated EGFR-positive tumors in NSG mice, outperforming non-covalent protein therapies.
• Treatment with CATIPs significantly limited systemic T cell activation, cytokine release, and xGVHD-associated morbidity.
• In melanoma models, CATIPs remodeled the tumor microenvironment, expanded CD8+ T cells, induced abscopal control, and generated durable protection against tumor rechallenge.

Conclusions:

• Covalent tumor anchoring of immunotherapeutic proteins converts local delivery into effective tumor-surface immune programming.
• CATIPs enable potent, tumor-specific, and durable antitumor immunity with reduced systemic immunopathology and off-target toxicity.
• CATIP-engineered tumor cells can serve as effective whole-cell vaccines, highlighting the platform's versatility.