Introduction: Triple-negative breast cancer (TNBC) is highly aggressive, with poor prognosis and limited effective treatments. Virus-like particles (VLPs)-based personalized vaccines offer a promising way to induce lasting antitumor immunity. While γδ T cells play roles in cancer, their interaction with nanoparticles is unclear. Administration route impacts efficacy: subcutaneous (s.c.) delivery within lymphatic watersheds targeting draining lymph nodes (dLNs), enhance local and systemic immune responses. Method: We developed plant-derived VLPs carrying TLR ligands and validated them by cryo-EM and biochemical assays. Using imaging flow cytometry and in vivo studies in the 4T1 s.c. TNBC model, we examined γδ T cell–VLP interaction and their role in vaccine efficacy. We compared three s.c. routes: systemic, targeting tdLNs, and targeting non-tdLNs. Survival was assessed under different dosing and ICI co-treatment. CD4+, CD8+, and γδ T cells were depleted to determine their contributions. Results: γδ T cells were expanded in dLNs and internalized VLPs post-vaccination. γδ subsets showed distinct activation. tdLN-targeted delivery, especially with ICI, gave the best outcomes. Depletion of CD4+, CD8+, or γδ T cells impaired efficacy, showing all are essential. Despite their rarity, γδ T cells were key to early tumor control. Conclusion: Our study highlights a crucial early role for γδ T cells in VLP-based cancer vaccination. Efficacy improved with ICI co-treatment and tdLN-targeted delivery, supporting inclusion of rare immune subsets like γδ T cells in cancer immunotherapy.