Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial and temporal heterogeneity of TAMs within the tumor microenvironment (TME), highlighting their diverse subtypes, origins, and functions. Advanced technologies such as single-cell sequencing and spatial multi-omics have elucidated the intricate interactions between TAMs and other TME components, revealing the mechanisms behind their recruitment, polarization, and distribution. Key findings demonstrate that TAMs support tumor vascularization, promote epithelial-mesenchymal transition (EMT), and modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing tumor invasiveness and metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways and overcoming drug resistance. This review underscores the potential of targeting TAMs to develop innovative cancer therapies, emphasizing the need for further research into their spatial characteristics and functional roles within the TME.

Macrophages are potent immune effector cells in innate immunity and exert dual-effects in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) make up a significant portion of TME immune cells. Similar to M1/M2 macrophages, TAMs are also highly plastic, and their functions are regulated by cytokines, chemokines and other factors in the TME. The metabolic changes in TAMs are significantly associated with polarization towards a protumour or antitumour phenotype. The metabolites generated via TAM metabolic reprogramming in turn promote tumor progression and immune tolerance. In this review, we explore the metabolic reprogramming of TAMs in terms of energy, amino acid and fatty acid metabolism and the potential roles of these changes in immune suppression.

Immune checkpoint molecules, also known as cosignaling molecules, are pivotal cell-surface molecules that control immune cell responses by either promoting (costimulatory molecules) or inhibiting (coinhibitory molecules) a signal. These molecules have been studied for many years. The application of immune checkpoint drugs in the clinic provides hope for cancer patients. Recently, the poliovirus receptor (PVR)-like protein cosignaling network, which involves several immune checkpoint receptors, i.e., DNAM-1 (DNAX accessory molecule-1, CD226), TIGIT (T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM)), CD96 (T cell activation, increased late expression (TACLILE)), and CD112R (PVRIG), which interact with their ligands CD155 (PVR/Necl-5), CD112 (PVRL2/nectin-2), CD111 (PVRL1/nectin-1), CD113 (PVRL3/nectin-3), and Nectin4, was discovered. As important components of the immune system, natural killer (NK) and T cells play a vital role in eliminating and killing foreign pathogens and abnormal cells in the body. Recently, increasing evidence has suggested that this novel cosignaling network axis costimulates and coinhibits NK and T cell activation to eliminate cancer cells after engaging with ligands, and this activity may be effectively targeted for cancer immunotherapy. In this article, we review recent advances in research on this novel cosignaling network. We also briefly outline the structure of this cosignaling network, the signaling cascades and mechanisms involved after receptors engage with ligands, and how this novel cosignaling network costimulates and coinhibits NK cell and T cell activation for cancer immunotherapy. Additionally, this review comprehensively summarizes the application of this new network in preclinical trials and clinical trials. This review provides a new immunotherapeutic strategy for cancer treatment.

The vulnerability of tumor cells to lipid peroxidation, driven by redox imbalance and lipid overabundance within the tumor microenvironment (TME), has become a focal point for novel antitumor strategies. Ferroptosis, a form of regulated cell death predicated on lipid peroxidation, is emerging as a promising approach. Beyond their role in directly eliminating tumor cells, lipid peroxidation and its products, such as 4-hydroxynonenal (HNE), exert an additional influence by damaging DNA and shaping an environment conducive to tumor growth and metastasis. This process polarizes macrophages towards a pro-inflammatory phenotype, dampens the antigen-presenting capacity of dendritic cells (DCs), and undermines the cytotoxic functions of T and NK cells. Furthermore, it transforms neutrophils into pro-tumorigenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). The lipid peroxidation of stroma cells also contributes to tumor progression. Although advanced nanotherapies have shown the ability to target tumor cells precisely, they often overlook the nuanced effects of lipid peroxidation products. In this review, we highlight a synergistic mechanism in which lipid peroxidation products and ferroptosis contribute to an immunosuppressive state that is temporally distinct from cell death. This insight broadens our understanding of ferroptosis-derived immunosuppression, encompassing all types of immune cells within the TME. This review aims to catalyze further research in this underexplored area, emphasizing the potential of lipid peroxidation products to hinder the clinical translation of ferroptosis-based therapies. Graphical abstract

Long noncoding RNA H19 (H19) is an imprinting gene with only maternal expression that is involved in regulating different processes in various types of cells. Previous studies have shown that abnormal H19 expression is involved in many pathological processes, such as cancer, mainly through sponging miRNAs, interacting with proteins, or regulating epigenetic modifications. Accumulating evidence has shown that several oncogenic signaling pathways lead to carcinogenesis. Recently, the regulatory relationship between H19 and oncogenic signaling pathways in various types of cancer has been of great interest to many researchers. In this review, we discussed the key roles of H19 in cancer development and progression via its regulatory function in several oncogenic signaling pathways, such as PI3K/Akt, canonical Wnt/β-catenin, canonical NF-κB, MAPK, JAK/STAT and apoptosis. These oncogenic signaling pathways regulated by H19 are involved in cell proliferation, proliferation, migration and invasion, angiogenesis, and apoptosis of various cancer cells. This review suggests that H19 may be a novel therapeutic target for cancers treatment by regulating oncogenic signaling pathways.