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

## TL;DR

A new strategy targets immune responses to reduce cancer growth and lung toxicity when combining vaccines with immune checkpoint inhibitors.

## Contribution

A homologous lymphoid organ-targeted strategy is introduced to enhance immunotherapy efficacy while minimizing pneumonitis.

## Key findings

- Targeted co-localization of tumor vaccines and anti-PD1 reduces tumor growth and CIP severity.
- Precise regulation of CD8+ T cells improves tumor-specific cytotoxicity and infiltration.
- Homologous targeting minimizes off-target immune-related toxicities.

## Abstract

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.

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•Tumor vaccines with αPD1 boost anti-tumor efficacy but raise CIP risk.•CD8+ T cells are closely associated with the occurrence of CIP.•Homologous targeted delivery strategy enables precise regulation of CD8+ T cells.•Increasing tumor-specific T cells with PD1-blockade may reduce CIP risk.

Tumor vaccines with αPD1 boost anti-tumor efficacy but raise CIP risk.

CD8+ T cells are closely associated with the occurrence of CIP.

Homologous targeted delivery strategy enables precise regulation of CD8+ T cells.

Increasing tumor-specific T cells with PD1-blockade may reduce CIP risk.