In situ genetic engineering of tumors for long-lasting and systemic immunotherapy

Area of Science:

• Biotechnology
• Immunology
• Nanomedicine

Background:

• Cancer immunotherapy research faces challenges in effectiveness and broad applicability.
• Current cellular therapies require complex procedures, increasing costs and limiting accessibility.

Purpose of the Study:

• To develop a general, cost-effective approach for endogenous patient-specific cellular therapy.
• To create a method for reprogramming cancer cells in situ without prior tumor antigen knowledge or ex vivo manipulation.

Main Methods:

• Synthetic, biodegradable nanoparticles were engineered to reprogram cancer cells and their microenvironment.
• Nanoparticles induced coexpression of 4-1BBL and IL-12 in cancer cells, turning them into tumor-associated antigen-presenting cells (tAPCs).
• The approach was tested in B16-F10 melanoma and MC38 colorectal carcinoma mouse models, often combined with checkpoint blockade.

Main Results:

• Reprogramming nanoparticles significantly reduced tumor growth in mouse models.
• Complete tumor clearance and long-term survival were observed in some cases.
• Treated mice developed resistance to subsequent tumor rechallenge, indicating durable immune memory.
• In vitro and in vivo analyses confirmed a potent, systemic, cell-mediated cytotoxic immune response.

Conclusions:

• Locally delivered tAPC-reprogramming nanoparticles can elicit a systemic, tumor-specific immune response.
• This nanomedicine approach bypasses the need for a priori tumor antigen identification.
• The technology holds significant translational potential for broadly accessible and cost-effective cancer immunotherapy.