# Development of Au x Cu y Pd z Nanocomposites as Therapeutic Agents: Enhancing Cancer Treatment through Autophagy Modulation and Immune-Associated Effects

## TL;DR

This paper introduces a new type of nanocomposite that enhances cancer treatment by modulating autophagy and boosting immune responses.

## Contribution

A Cu-templated synthesis method creates Au x Cu y Pd z nanocomposites with enhanced therapeutic effects through autophagy and immune modulation.

## Key findings

- Au x Cu y Pd z nanocomposites increase autophagy and lipid peroxidation in cancer cells.
- The nanocomposites reduce immune escape proteins like IDO1, PD-L1, and CD47 in tumor models.
- Photothermal therapy with low laser power enhances antitumor immune cell infiltration.

## Abstract

The development of multimetallic nanoparticles for cancer
treatment
represents a significant advancement in the field of nanomedicine.
We introduce a Cu-templated synthesis method to create Au
x
Cu
y
Pd
z
hollow nanomicrostructures, wherein gold atoms stabilize copper
(Cu) and facilitate the incorporation of palladium (Pd) through oxidation
and coreduction processes. These ternary nanocomposites demonstrate
enhanced cellular uptake via the copper transporter CTR1/2-mediated
pathway and exhibit superior catalytic activity for the reaction of
hydrogen peroxide to generate hydroxyl radicals. The presence of both
Cu and Pd triggers significant autophagic responses, increases lipid
peroxidation, and disturbs copper metabolism, as indicated by the
increased expression of autophagy-related proteins and mitochondrial
reactive oxygen species, ultimately leading to selective cancer cell
death. The synergistic effects of these three metals not only increase
autophagy but also promote the degradation of immune escapable proteins,
including IDO1, PD-L1, and CD47. Based on the Cu/Pd element-induced
biochemical stimulation, we conducted a proof-of-concept in vivo validation
using a murine orthotopic bladder tumor model to demonstrate that
Au–Cu–Pd ternary nanoparticles enhance autophagy and
ferroptosis, thereby reversing the immunosuppressive tumor microenvironment
by reducing immune escape proteins. These effects increased the infiltration
of antitumor immune cells, with further enhancement from photothermal
therapy at a low laser power density and sample dose. Our findings
offer valuable insights into designing multimetallic nanoparticles
through element chemistry for cancer therapy, highlighting their potential
as effective modulators of autophagy.