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.