Biomimetic Nanoparticles with Dual Targeting for Hepatocellular Carcinoma Promote Tumor Immune System Activation by Enhancing Extracellular ATP Homeostasis

Chemodynamic
therapy (CDT) plays a crucial role in transforming
the tumor microenvironment by inducing immunogenic cell death (ICD)
to eliminate cancer cells. Nonetheless, the effectiveness of CDT in
eliciting antitumor immunity is somewhat constrained. The persistent
presence of immunosuppressive cells, such as myeloid-derived suppressor
cells (MDSCs), in the tumor offsets some of the ICD effects triggered
by CDT. Moreover, extracellular adenosine triphosphate (eATP), a crucial
damage-related molecular pattern that initiates ICD, is quickly degraded
into adenosine, an immunosuppressive metabolite, by CD39 molecules
prevalent in the tumor environment, thereby evading immune destruction.
In this report, we introduce a nanomaterial, CP@HMM (copper-doped
carbon dots and POM1 encapsulated by a hybrid membrane composed of
Hepa1–6 and a MDSCs membrane), which targets liver cancer cells
and MDSCs and inhibits the ATP–adenosine metabolic pathway.
The hybrid membrane, derived from hepatocellular carcinoma (HCC) cells
and MDSCs, facilitates the targeted delivery of copper-doped carbon
dots (Cu-CDs) to these cells. The potent Fenton-like reactions and
the cytotoxicity of copper ions allow CP@HMM to not only kill tumor
cells but also eradicate intratumoral MDSCs. Additionally, the CD39
inhibitor POM1 within the system prevents the degradation of eATP
induced by the Cu-CDs treatment. This leads to increased eATP levels
and drives antitumor immunity activation, including macrophage pyroptosis
and dendritic cell maturation, which suppresses primary tumor progression
and distant metastases while fostering immune memory to prevent tumor
recurrence. Our findings suggest that CP@HMM is an effective drug-delivery
system and offers a potential therapeutic alternative for patients
with HCC, promising advancements in combined tumor immunotherapy strategies.