# Combined Photothermal and mTOR‐Targeted Therapy Overcomes Immune Evasion and Enhances Checkpoint Blockade Efficacy in Metastatic Triple‐Negative Breast Cancer

## TL;DR

A new treatment combining heat therapy and mTOR inhibition boosts immune response and fights metastatic breast cancer.

## Contribution

A pH/NIR-II-responsive nanocomposite is developed to combine photothermal therapy with mTOR inhibition, enhancing immune checkpoint blockade.

## Key findings

- Photothermal therapy activates mTOR, promoting tumor immune evasion.
- The nanocomposite synergizes with PD-1 blockade to amplify antitumor immunity.
- The triple-combination regimen effectively targets distant metastases in murine models.

## Abstract

Triple‐negative breast cancer, a representative immune “cold” tumor, resists immune checkpoint blockade (ICB). A promising strategy to overcome this limitation involves combining photothermal therapy (PTT) with ICB. Here, it is demonstrated that while PTT enhances antitumor immunity by inducing immunogenic cell death (ICD), it paradoxically activates the oncogenic mTOR pathway, driving tumor immune evasion. To address this, ASPPR∩A, a mTOR inhibitor‐loaded and pH/NIR‐II‐responsive gold nanocomposite delivering localized hyperthermia and mTOR inhibition, are developed. The nanocomposite selectively targets tumor cells and efficiently converts NIR‐II light into hyperthermia upon laser irradiation. In vitro, the nanocomposite‐mediated photothermal‐mTOR dual‐therapy synergistically enhances ICD and MHC‐I antigen presentation. In murine TNBC models, this combination significantly amplifies ICD and T‐cell infiltration, and synergizes with PD‐1 blockade. Notably, this triple‐combination regimen effectively eliminates distant metastases via systemic antitumor immune response. The findings reveal the paradoxical role of PTT, establishing a photothermal‐targeted‐immune combinatorial paradigm for treating metastatic immune “cold” tumors.

This study reveals that photothermal therapy, while inducing immunogenic cell death in triple‐negative breast cancer, paradoxically activates the oncogenic mTOR pathway to drive immune evasion. To counter this, a smart nanocomposite is engineered to co‐deliver localized hyperthermia and mTOR inhibition. This dual‐therapy synergizes with PD‐1 blockade, creating a powerful combinatorial strategy against immunologically “cold” tumors.