Acute myeloid leukemia (AML) is a heterogenous malignant hemopathy, and although new drugs have emerged recently, current treatment options still show limited efficacy. Therapy resistance remains a major concern due to its contribution to treatment failure, disease relapse, and increased mortality among patients. The underlying mechanisms of resistance to therapy are not fully understood, and it is crucial to address this challenge to improve therapy. Macrophages are immune cells found within the bone marrow microenvironment (BMME), of critical importance for leukemia development and progression. One defining feature of macrophages is their plasticity, which allows them to adapt to the variations in the microenvironment. While this adaptability is advantageous during wound healing, it can also be exploited in cancer scenarios. Thus, clinical and preclinical investigations that target macrophages as a therapeutic strategy appear promising. Existing research indicates that targeting macrophages could enhance the effectiveness of current AML treatments. This review addresses the importance of macrophages as therapeutic targets including relevant drugs investigated in clinical trials such as pexidartinib, magrolimab or bexmarilimab, but also provides new insights into lesser-known therapies, like macrophage receptor with a collagenous structure (MACRO) inhibitors and Toll-like receptor (TLR) agonists.

With the advent of new therapeutic approaches, there is hope that anticancer treatment will eventually be possible without the use of chemotherapy. Efficient immunotherapeutic options have recently emerged in many cancers, offering a less aggressive approach, with overall better tolerance, making them also suitable for frail patients. Response to immunotherapy relies on the availability, functionality, and efficacy of the host’s immune effector mechanisms. One of the key factors determining the efficacy of immunotherapy is the tumor microenvironment, which encompasses various immune effectors, including macrophages, which play a crucial role in regulating immune responses through phagocytosis and antigen presentation. Macrophages are prototypically divided, according to their polarization, into either the pro-inflammatory M1 type or the anti-inflammatory M2 type. In the tumor microenvironment, M2-polarized macrophages, known as tumor-associated macrophages (TAMs), are the predominant phenotype and are associated with tumor progression. The M1/M2 paradigm contributes to the understanding of tumor progression. Due to the variable microenvironment, the mechanisms regulating TAMs can vary across different cancers. Variations in TAM polarization may account for the different treatment responses in patients with similar diseases. This paper investigates the connection between TAMs, disease progression, and treatment responses in the most frequent solid hematologic cancer, diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), the most prevalent subtype of non-Hodgkin lymphoma (NHL), is an aggressive and fairly heterogeneous group with diverse clinical, pathological, and molecular features. Despite the success of first-line immunochemotherapy, relapsed or treatment-resistant forms remain a clinical challenge. Consequently, minimally invasive markers are needed to predict refractoriness. Recently, circulating microRNAs (miRNAs) have emerged as highly stable, promising biomarkers. MiRNAs such as miR-21, miR-155, miR-222-3p, and the miR-17~92 cluster act as oncogenes that promote tumor survival, while others, such as miR-34, miR-181a, miR-144, miR-101, miR-10a, and miR-320, act as tumor suppressors. Despite multiple recent publications that have correlated dysregulated miRNAs with diagnostic and prognostic importance, the clinical translation has not been fully addressed. Overall, this review provides an updated perspective on the potential of miRNAs in DLBCL and outlines key challenges and future directions for their integration into precision oncology, as miRNAs can remodel the clinical management of DLBCL by enabling earlier diagnosis, improved prognostication, and personalized treatment approaches.