NIR-II Imaging-Guided Phototherapy-Induced Senescence Reprograms Immunosuppressive Tumor Microenvironment for Potent...

Area of Science:

• Oncology
• Immunology
• Nanomedicine

Background:

• Cellular senescence is a key tumor suppressor mechanism involving cell-cycle arrest and regulating the tumor microenvironment (TME).
• Exploiting senescence inducers to promote senescence-associated secretory phenotypes (SASPs) and enhance immune infiltration is an underexplored strategy.
• Triple-negative breast cancer (TNBC) presents a highly immunosuppressive TME, necessitating novel therapeutic approaches.

Purpose of the Study:

• To develop a phototherapy-based strategy for inducing senescence and overcoming the immunosuppressive TME in TNBC.
• To investigate the potential of a nanoplatform delivering an Aurora kinase inhibitor and a phototheranostic molecule for combined therapy.
• To evaluate the impact of this approach on SASP expression, immune cell infiltration, and tumor regression.

Main Methods:

• Development of a reactive oxygen species-responsive nanoplatform co-delivering alisertib (Aurora kinase inhibitor) and a near-infrared emissive molecule.
• Application of 808 nm laser phototherapy to induce alisertib release, oxidative stress, and cellular senescence.
• Analysis of SASP secretion, immune cell populations (cytotoxic T lymphocytes, myeloid-derived suppressor cells, regulatory T cells), and tumor growth in a TNBC model.
• Assessment of immunological memory and systemic toxicity.

Main Results:

• Phototherapy induced alisertib release and oxidative stress, leading to senescence and SASP secretion.
• The nanodrug remodeled the TME by activating cytotoxic T lymphocytes and depleting immunosuppressive cells.
• Efficient tumor regression was achieved, accompanied by the establishment of durable immunological memory.
• The treatment demonstrated no significant systemic toxicity.

Conclusions:

• Senescence induction via phototherapy is a promising strategy to overcome immunosuppressive TMEs in TNBC.
• The developed nanoplatform effectively integrates phototherapy-enhanced drug delivery with SASP-driven immunosurveillance.
• This approach represents a potential next-generation photoimmunotherapy for cancer treatment.