mRNA lipid-nanoparticle-mediated mitochondrial apoptosis augments adoptive T cell immunotherapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptive T cell therapy (ACT) shows promise for cancer immunotherapy but has limited efficacy against solid tumors.
• Modulating mitochondrial apoptosis (mtApoptosis) priming in cancer cells is an emerging strategy to enhance ACT.
• Current ACT approaches require optimization to overcome tumor resistance and immunosuppression.

Purpose of the Study:

• To develop and evaluate an mRNA-based combinational strategy to enhance ACT by inducing mtApoptosis in cancer cells.
• To investigate the mechanisms by which this strategy augments antitumor immunity and T cell function.
• To assess the therapeutic efficacy of the combined approach in preclinical cancer models.

Main Methods:

• Development of mRNA lipid nanoparticles encoding BH3 domains to trigger mtApoptosis.
• In vitro assays to assess synergistic tumor cell killing and apoptotic threshold reduction.
• In vivo studies combining mRNA therapy with ACT in solid tumor models.
• Single-cell transcriptomics to analyze T cell responses and tumor microenvironment modulation.

Main Results:

• The mRNA-based formulation effectively induced robust mtApoptosis and immunogenic cell death in cancer cells.
• Combination therapy synergistically enhanced tumor cell killing in vitro and improved therapeutic efficacy in vivo.
• The treatment boosted endogenous T cell cytotoxicity, mitigated ACT-induced T cell dysfunction, and remodeled the immunosuppressive microenvironment.
• Single-cell transcriptomics revealed reprogramming of effector T cells towards memory-like states with enhanced TCR diversity.

Conclusions:

• A combinatorial mRNA-based strategy effectively primes cancer cells for apoptosis, significantly augmenting ACT efficacy.
• This approach offers a novel mechanism for enhancing cancer immunotherapy by improving T cell function and overcoming tumor resistance.
• The findings provide mechanistic insights into leveraging mtApoptosis for improved adoptive T cell therapy outcomes.