Reprogramming Tumor-Associated Macrophages

Team: Dr. Lena Graß, Dalia Nour, Anton Bomhard, Hannah Britzelmaeir, Sabine Brummer

A New Approach to Lung Cancer Therapy

Lung cancer is one of the leading causes of cancer-related deaths worldwide, and despite major advances, effective treatments are still limited. Recent progress with immune checkpoint inhibitors has revealed the crucial role of the tumor microenvironment (TME) in cancer progression. Tumor-associated macrophages (TAMs) are a significant immune cell population in the TME that can adopt different functional states ranging from anti-tumorigenic to pro-tumorigenic phenotypes. The latter contribute to tumor growth, metastasis, and immune evasion by secreting factors that suppress immune responses and promote tissue remodeling. Targeted reprogramming of disease-promoting macrophages thus represents a promising strategy to halt cancer development and progression.

Intracellularly, TAMs utilize non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs to regulate their gene expression and shift between polarization states. To understand the mechanisms driving macrophage polarization in the TME, we combine single-cell RNA sequencing of tumorous and non-tumorous tissues with cell-based CRISPR-CasRx screens and in vivo disease models. To repolarize TAMs from a tumor-promoting to an anti-tumorigenic state, we are developing small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) to target polarization-specific ncRNAs. These therapeutic nucleotides are conjugated to sugar molecules that selectively bind to surface markers unique to TAMs. An application strategy that ensures targeted delivery and therapeutic precision while minimizing off-target effects.