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.

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.

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