Triple-negative breast cancer (TNBC) is one of the most aggressive and treatment-resistant subtypes of breast cancer, accounting for 15-20% of all cases. 

Unlike other breast cancers, TNBC lacks targetable receptors, leaving patients dependent largely on chemotherapy, with limited treatment options.

Even immunotherapy - an approach that has transformed cancer treatment - benefits fewer than 20% of TNBC patients, largely because tumours contain large numbers of regulatory T cells (Tregs) that suppress the immune system and prevent it from effectively attacking cancer cells.

A research team led by Professor Eijiro Miyako at the Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, has developed a multifunctional nanoplatform called B-LM-DMX-αCD25 that simultaneously addresses three key barriers to effective TNBC immunotherapy.

The platform uses gallium-based liquid metal nanoparticles, a photothermal material with a conversion efficiency exceeding 54%, coated with whole-blood components.

This camouflage makes the particles appear as "self" to the body, allowing them to evade immune clearance and accumulate in tumours at five times the efficiency of conventional nanoparticles.

Once at the tumour site, the platform deploys three synchronised therapeutic mechanisms. First, anti-CD25 antibodies on the nanoparticle surface selectively eliminate intratumoural Tregs, releasing the "immunological brake" that suppresses anti-cancer immunity.

Second, near-infrared laser irradiation heats the tumour to 58°C within five minutes, destroying cancer cells and triggering immunogenic cell death. This process releases tumour antigens and danger signals that alert the immune system. 

Third, the STING agonist DMX, released on demand by laser activation, activates innate immunity by promoting dendritic cell maturation and stimulating the production of interferon-β, which drives tumour-specific cytotoxic T cell responses.

In preclinical studies using orthotopic mouse models of drug-resistant TNBC, the platform achieved 100% complete tumour regression, suppressed pulmonary metastases by more than 90%, and extended median survival beyond 70 days.

Comprehensive molecular analysis confirmed robust immune activation, including a more than 13-fold increase in CD3-positive T cells and an 11-fold increase in dendritic cells within treated tumours.

The researchers' strategy addresses the immunosuppressive environment that makes TNBC difficult to treat by combining tumour destruction with targeted removal of Tregs and activation of innate immunity.

By coordinating these three mechanisms, the platform converts an immunologically "cold" tumour environment into one that is more responsive to the immune system.

The whole-blood camouflage strategy also provides a straightforward approach to biomimetic nanoparticle engineering.

By using components of blood to help nanoparticles evade immune clearance, the researchers aim to improve their accumulation at tumour sites while retaining their therapeutic functions.

The approach could potentially be adapted to other solid tumours in which immune suppression limits the effectiveness of immunotherapy.

The researchers plan to expand the platform to other solid tumour types, particularly pancreatic and ovarian cancers, where immune suppression by Tregs is also a significant challenge.

They are also developing NIR-II laser-compatible formulations to extend photothermal therapy to deeper tumours.

In parallel, they are preparing GLP-compliant repeat-dose toxicology studies as part of a preclinical development package aimed at eventual clinical translation.

"We are combining three different approaches in a single nanoparticle to overcome the mechanisms that allow these tumours to evade the immune system," said Professor Eijiro Miyako.

"Our next step is to determine whether this strategy can be applied safely and effectively to other types of solid tumours and eventually translated toward clinical use."

The findings were published in Advanced Science.

Article: Blood Cell-Camouflaged Liquid Metal Nanoconjugates Orchestrate Treg Depletion and STING-Amplified Photothermal Immunity for Metastatic Triple-Negative Breast Cancer Therapy

Source: Tohoku University