# NIR-II Nanomedicine Engineered CAR-NK Cells for Precision Navigation and Potentiating Lung Cancer Immunotherapy by Remodeling Tumor Microenvironment

## TL;DR

This paper introduces a new CAR-NK cell therapy for lung cancer that uses nanomedicine to improve tumor targeting and immune response.

## Contribution

A novel CAR-NK biohybrid system is developed using NIR-II nanomedicine and Smad3 inhibition to enhance tumor infiltration and immune activation.

## Key findings

- NIR-II fluorescence imaging enables real-time tracking and precise tumor localization.
- NIR-II photothermal therapy disrupts tumor barriers and enhances CAR-NK cell infiltration.
- Smad3 inhibition reduces ECM deposition and boosts immune activation in the tumor microenvironment.

## Abstract

Despite the prominent
success against hematologic malignancies
in clinical settings, chimeric antigen receptor NK (CAR-NK) cell immunotherapy
is still hindered in lung cancer tumors owing to insufficient infiltration
and poor immune activation induced by the immunosuppressive tumor
microenvironment (TME). Herein, a nanoengineered CAR-NK biohybrid
(CK-PSI) was constructed by conjugating nanomedicine (PSI NPs) containing
a near-infrared II (NIR-II) polymer and a specific small-molecule
inhibitor of Smad3 (SIS3) to the surface of metabolic glycan-engineered
CAR-NK cells via a bioorthogonal reaction. Anti-B7H3 CAR modification
on cell vectors offers selectively targeted delivery of hitchhiking
NIR-II nanomedicine into lung cancer tumors, simultaneously enabling
real-time tracking of CAR-NK cells and precise localization of deep-seated
tumors through NIR-II fluorescence imaging. NIR-II excitation mild
photothermal therapy not only destroys tumor cells by thermal ablation
but also promotes the infiltration and penetration of CK-PSI through
the rupture of physical barriers within tumor tissues. More importantly,
the in situ release of the Smad3 inhibitor further
reduces extracellular matrix (ECM) deposition through TGF-β
signaling pathway blockade in the TME, thereby boosting the infiltration
and immune activation of CAR-NK cells. The bioorthogonal nanohybrid
with NIR-II phototheranostic triggered cell localization and immunomodulatory
capabilities provides a new paradigm for potentiating the infiltration
and immune activation efficiency of CAR-NK cells against solid tumors.