Precise regulation of cancer vaccine and immune checkpoint inhibitor synergy potentiates immunotherapy with reduced immune-related pneumonitis.

The combination of cancer vaccine and an immune checkpoint inhibitor (ICI) function synergistically to induce effective antitumor immune responses. However, their clinical application is constrained by exacerbated immune-related adverse events (irAEs), notably checkpoint inhibitor-associated pneumonitis (CIP). To address this challenge, a peripheral lymphoid organ-targeted strategy was developed to spatiotemporally modulate T-cell responses through the co-localization of tumor vaccines and anti-PD1 (αPD1). This approach substantially reduced tumor growth and CIP severity by attenuating nonspecific T-cell infiltration in the lungs. In contrast, when tumor vaccines and αPD1 failed to precisely target the same T cell population, the enhanced therapeutic efficacy was at the cost of increased off-target CIP. As a consequence, combined tumor-specific T cells with PD1-blockade performed superior tumor-specific cytotoxicity and preferential tumor infiltration, further augmenting anti-tumor effects while minimizing CIP. These findings provide a homologous lymphoid organ-targeted paradigm that optimizes anti-tumor immune responses with reduced immune-related toxicities, offering a promising strategy for safer and more effective cancer immunotherapy.