Cancer remains a significant challenge for public healthcare systems worldwide. Within the realm of cancer treatment, considerable attention is focused on understanding the tumor microenvironment (TME)—the complex network of non-cancerous elements surrounding the tumor. Among the cells in TME, tumor-associated macrophages (TAMs) play a central role, traditionally categorized as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Within the TME, M2-like TAMs can create a protective environment conducive to tumor growth and progression. These TAMs secrete a range of factors and molecules that facilitate tumor angiogenesis, increased vascular permeability, chemoresistance, and metastasis. In response to this challenge, efforts are underway to develop adjuvant therapy options aimed at reprogramming TAMs from the M2 to the anti-tumor M1 phenotype. Such reprogramming holds promise for suppressing tumor growth, alleviating chemoresistance, and impeding metastasis. Nanotechnology has enabled the development of nanoformulations that may soon offer healthcare providers the tools to achieve targeted drug delivery, controlled drug release within the TME for TAM reprogramming and reduce drug-related adverse events. In this review, we have synthesized the latest data on TAM polarization in response to TME factors, highlighted the pathological effects of TAMs, and provided insights into existing nanotechnologies aimed at TAM reprogramming and depletion.

In the tumor microenvironment, M2 tumor-associated macrophages play a crucial role in promoting tumor growth, vascularization, and metastasis through their anti-inflammatory and tissue-repairing functions. To reprogram M2 cells into a more benign M1 phenotype and enhance the patient’s intrinsic immune response against cancer, siRNA and small molecules are used, which can be encapsulated into nanoparticles to enhance their stability, circulation time, and bioavailability. Albumin nanoparticles are ideal candidates for the delivery of such cargo because of their low toxicity, biocompatibility, biodegradability, prolonged circulation in the bloodstream, and feasible particle modification. In this study, we optimized a one-step desolvation method using the standard cross-linker glutaraldehyde and D-mannose as a second cross-linker for the synthesis of mannosylated albumin nanoparticles. The obtained nanoparticles demonstrated favorable physical characteristics, high encapsulation efficiency, and the most effective targeting into activated M2 macrophages overexpressing the mannose receptor in comparison to M1 macrophages and cancer cells in vitro.