The tumor microenvironment (TME) is a complex and dynamic ecosystem crucial for cancer progression and therapeutic response. Tumors actively shape this environment to facilitate immune evasion, often by recruiting and reprogramming various immunosuppressive cells. Among these, tumor-associated macrophages (TAMs) are one of the most abundant and pivotal components. High infiltration of TAMs in solid tumors is frequently associated with poor patient prognosis, resistance to conventional therapies, and failure of immune checkpoint blockade (ICB). For instance, in certain KRAS-mutated non-small cell lung cancer, tumor cells can secrete specific cytokines to induce the aggregation of macrophages, which in turn establishes an immunosuppressive microenvironment.

TAMs promote tumorigenesis through several mechanisms: they suppress the cytotoxic functions of T cells, foster angiogenesis and tissue remodeling, and facilitate tumor cell invasion and metastasis. While the paradigm of M1 (pro-inflammatory) versus M2 (anti-inflammatory) macrophages provided an initial framework, it is now clear that TAMs exhibit remarkable heterogeneity and plasticity, existing in a spectrum of functional states that are dynamically shaped by signals within the TME. This complexity is a primary reason why existing TAM-targeted therapies, such as CSF-1R inhibitors or antibodies against CD40/CD47, have shown limited efficacy in broad patient populations. The overall low response rates underscore a critical knowledge gap in our understanding of the diverse TAM subpopulations and their precise roles in tumor biology.

To break this therapeutic deadlock, a better understanding of TAM biology is needed. The advent of multi-omics technologies—including genomics, transcriptomics (at both bulk and single-cell levels), proteomics, metabolomics, and spatial-omics—offers an unprecedented opportunity to dissect the molecular complexity of TAMs. By integrating these high-dimensional datasets, we can create a comprehensive atlas of TAM states, identify novel molecular pathways governing their function, and uncover their spatial organization and interactions within the native TME. This multi-pronged approach is essential for identifying and validating the next generation of robust therapeutic targets on TAMs, ultimately aiming to reprogram these cells from tumor-promoting to tumor-fighting agents.

The objective of this Research Topic collection is to gather cutting-edge research that utilizes multi-omics approaches to unravel the complex roles of TAMs in solid tumors. We aim to create a forum for studies that illuminate TAM heterogeneity, function, and therapeutic vulnerabilities. We welcome Original Research, Reviews, and Perspectives that explore the multifaceted biology of TAMs and their potential as therapeutic targets. The areas of interest include, but are not limited to:

- Multi-Omics Characterization of TAM Heterogeneity: Studies using single-cell RNA-seq, spatial transcriptomics, proteomics, or other omics to identify and characterize distinct TAM subsets and their unique molecular signatures in different tumor types.
- Functional States and Plasticity of TAMs: Research investigating the molecular mechanisms (signaling pathways, metabolic reprogramming, epigenetic regulation) that govern the functional polarization and plasticity of TAMs within the TME.
- TAM-Tumor Cell Crosstalk: Elucidating the bidirectional communication between TAMs and cancer cells that drives tumor progression, metastasis, and the establishment of an immunosuppressive niche.
- Spatial Organization and Interactions within the TME: Analyzing the spatial distribution of different TAM subsets in relation to other immune cells (T cells, NK cells, dendritic cells), stromal cells, and blood vessels, and how these spatial relationships impact immune responses.
- Prognostic and Predictive Biomarkers: Identifying TAM-related multi-omics signatures that can predict patient prognosis or response to specific therapies, including immune checkpoint inhibitors and existing TAM-targeting agents.
- TAMs as Drivers of Therapy Resistance: Investigating the mechanisms by which TAMs contribute to resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy.
- Novel Therapeutic Targets and Strategies: Discovery and preclinical validation of new therapeutic targets on or related to TAMs, identified through multi-omics analysis. This includes novel cell surface receptors, metabolic vulnerabilities, or secreted factors.
- Therapeutic Reprogramming of TAMs: Exploring innovative strategies to “re-educate” or reprogram pro-tumoral TAMs into anti-tumoral effector cells, and assessing the efficacy of such approaches in preclinical models.

Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic.

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Multi-Omics Interrogation of Tumor-Associated Macrophages: Paving the Way for Next-Generation Cancer Immunotherapies