Targeting Myeloid Cells in the Tumor Microenvironment

Dear Colleagues,

The field of targeting myeloid cells in the tumor microenvironment (TME) centers on reversing their capacity to shield the tumor, thereby generating a novel class of anti-tumor therapies. Myeloid cells, such as Tumor-Associated Macrophages (TAMs), dendritic cells, neutrophils, and other granulocytes, are critical regulators of immune evasion and often represent the key to treatment resistance. A key question is whether tumor tolerance is induced non-specifically through an overwhelmingly immuno-suppressive milieu within a TME or through active tolerance for tumor antigens. Next to multiple immune suppressive signals within the TME, pro-inflammatory factors include cell death, intracellular fragments, and even viral or bacterial elements. Immune tolerance induced by tumors avoids long-term immune surveillance. Since TAMs are actively engaged in phagocytic processes and deploy Class II antigen presenting machinery, tolerance is an important mechanism of immune evasion, making TAMs both witnesses and accomplices of cancer’s overall advance.

Deciphering Myeloid Diversity, Function and Targeting

A core challenge is deciphering myeloid diversity, as these cells are highly plastic. Combining classical tissue and cell analysis with advanced techniques like single-cell sequencing are now defining distinct, specific functional subtypes across multiple lineages, including various polarization states of TAMs and different phenotypes of tumor-infiltrating leukocytes. This complexity necessitates function and key molecular determinant definition of each subset, whether pro- or anti-tumorigenic, to activate or inhibit immune responses, rather than just a combination of markers. Crucially, location and cell contacts matter. Spatial and cell contact analysis by advanced imaging are required to map different myeloid subsets and location within tumors, dictating their crucial interactions with cancer cells and adaptive immunity, to target treatment.

Current therapeutic development focuses on two main strategies: depletion versus reprogramming. Depletion aims to eliminate immunosuppressive populations, but this approach risks systemic side effects, complicated by continuous recruitment of new cells driven by TME signaling. Additionally, TAMs actively present tumor antigens to achieve tumor tolerance; a more sophisticated strategy is TAM reprogramming, to re-educate inhibitory myeloid cells into pro-inflammatory phenotypes that support adaptive immunity.

Dr. Tatiana I. Novobrantseva
Dr. Igor Feldman
Prof. Dr. Siamon Gordon
Guest Editors

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• macrophage
• tolerance
• repolarization
• TME
• cancer
• immuno-therapy therapeutics immunity