# Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy

## TL;DR

Researchers developed valrubicin-loaded immunoliposomes that target and reduce immunosuppressive cells in tumors, improving cancer immunotherapy effectiveness.

## Contribution

The study introduces a novel nanoparticle therapy that targets multiple immunosuppressive cell antigens to enhance anti-PD-1 treatment in resistant cancer models.

## Key findings

- Val-ILs reduce antigen expression on immunosuppressive cells like macrophages and T cells in the tumor microenvironment.
- Val-ILs enhance anti-PD-1 therapy efficacy in both responsive and resistant mouse cancer models.
- Val-ILs increase tumor-infiltrating lymphocytes and reprogram macrophages toward an anti-tumor phenotype.

## Abstract

We develop valrubicin-loaded immunoliposomes (Val-ILs), a nanoparticle-based therapy designed to target immunosuppressive cells that promote immune evasion in cancer. In vivo screening following intravenous administration in mice identifies nine relevant surface targets, including known immunoregulatory markers (LAG-3 and VEGFR2) and not-well-characterized candidates (CD11b, CD64, TIM1, CD200R3, CD204, CD49b, and SIGLEC-F). Within the tumor microenvironment, Val-ILs treatment broadly reduces the expression of these antigens on immunosuppressive populations, including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and T helper 17 cells, as well as on innate anti-tumor cells such as tumor-associated natural killer cells and tumor-infiltrating dendritic cells. Across four murine cancer models, two responsive (T and B lymphomas) and two resistant (orthotopic breast and lung cancers), Val-ILs decorated with antibodies against the nine targets significantly enhance anti-PD-1 efficacy. This combination boosts the presence of CD4+ and CD8+ tumor-infiltrating lymphocytes, reprograms tumor-associated macrophages toward an M1-like phenotype, and improves tumor control and metastasis reduction.

•Val-ILs target nine antigens expressed by pro-tumor immunosuppressive cells•Val-ILs affect key immunosuppressive populations in the TME, the spleen, and the lymph nodes•Val-ILs inhibit tumor growth in lymphoma, breast, and lung mouse cancer models•Val-ILs enhance anti-PD-1 therapy and overcome resistance in unresponsive tumors

Val-ILs target nine antigens expressed by pro-tumor immunosuppressive cells

Val-ILs affect key immunosuppressive populations in the TME, the spleen, and the lymph nodes

Val-ILs inhibit tumor growth in lymphoma, breast, and lung mouse cancer models

Val-ILs enhance anti-PD-1 therapy and overcome resistance in unresponsive tumors

Georgievski et al. report valrubicin-loaded immunoliposomes (Val-ILs) that target immunosuppressive cells in mouse cancer models. These Val-ILs affect the expression of nine antigens expressed by pro-tumor immunosuppressive cells, reprogram tumor-associated macrophages, increase tumor-infiltrating lymphocytes into the tumor microenvironment, and enhance anti-PD-1 efficacy. In murine models of both responsive and resistant cancers, this strategy restores anti-tumor immunity, improves tumor control, and limits metastasis.