Intratumoral Biodegradable Platform For Localized Multimodal Immunotherapy Delivery Enhances Tumor Eradication

Background: Tumor-infiltrating lymphocytes (TILs) play a crucial role in shaping the immune landscape of the tumor microenvironment (TIME), with elevated TIL counts in triple-negative breast cancer (TNBC) linked to better outcomes. While immunotherapy shows promise, its effectiveness can be compromised as cancer cells develop resistance, particularly in single- or dual-drug treatments. Strategies involving multiple drugs that target different immune pathways could offer improved efficacy, but their systemic administration is often limited by severe toxic side effects. Methods: We created a biodegradable nanofluidic drug-eluting seed (b-NDES) platform for the localized and sustained release of multiple immunotherapies. These b-NDES implants were designed to deliver a combination of immune checkpoint inhibitors (α-CTLA4), immune adjuvants (STING agonist, resiquimod [R848]), IL-12, and agonist antibodies (α-CD40) directly into the tumor in murine 4T1 and KPC cancer models. The effectiveness of this five-drug regimen in eliminating tumors was evaluated. A systemic immune response was assessed using an abscopal model, and immune memory was tested through rechallenge experiments. Results: The b-NDES platform significantly enhanced tumor suppression, with the five-drug combination achieving complete tumor eradication and prevention of lung metastasis in the majority of treated mice. The abscopal model demonstrated that b-NDES could also initiate systemic immune responses, causing regression in untreated tumors located at a distance. Mice in rechallenge experiments displayed strong immune memory, rejecting new tumor growth. Additionally, b-NDES-treated mice exhibited lower systemic toxicity, with stable body weight and minimal liver damage. Conclusion: The b-NDES platform offers a novel, localized approach to delivering multiple immunotherapeutic agents, resulting in effective tumor eradication, systemic immune activation, and durable immune memory while reducing systemic toxicity. These results highlight its potential to support safer, more effective treatment protocols for aggressive cancers such as TNBC.