The tumor microenvironment (TME) emerges as a unique challenge to oncotherapy due to its intricate ecosystem containing diverse cell types, extracellular matrix, secreted factors, and neovascularization, which furnish tumor growth, progression, invasion, and metastasis. Graphene oxide (GO)-based materials have garnered increasing attention in cancer therapy owing to their vast specific surface area, flexible lamellar structure, and electronic-photonic properties. Recently, interactions of GO with the TME have been broadly investigated, including trapping biomolecules, catalysis, cancer stem cell targeting, immunoreactions, etc., which inspires combinative therapeutic strategies to overcome TME obstacles. Herein, we summarize TME features, GO modulating various dimensions of the TME, and a TME-triggerable drug delivery system and highlight innovation and merits in combinative cancer therapy based on TME modulation. This review aims to offer researchers deeper insights into the interactions between versatile GO nanomaterials and the TME, facilitating the development of rational and reliable GO-based nanomedicines for advanced oncotherapy.

The transcription factor YY1 is significantly upregulated in M2 macrophages, which can facilitate the malignant progression of multiple cancers. However, the precise mechanisms underlying the influence of YY1-high M2 macrophages on prostate cancer (PCa) progression remain elusive. Therefore, this study aims to elucidate the specific mechanisms by which YY1-high M2 macrophages influence PCa progression. Cell proliferation was assessed through colony formation and CCK8 assays. To evaluate cell invasion and migration, Transwell and wound healing assays were utilized. We investigated the effects of exosomes derived from M2 macrophages overexpressing YY1 on PCa cells. Subsequently, circRNA microarrays and qRT-PCR identified a high level of hsa-circ-0000326 in exosomes. Nucleoplasmic isolation, luciferase reporter, RNA-pulldown assays elucidated the functions and downstream targets (miR-338-3p and AR) of hsa-circ-0000326. Chromatin immunoprecipitation sequencing, chromatin conformation capture, qRT-PCR, western blotting, and agarose-electrophoresis assays examined YY1's role in transcribing the hsa-circ-0000326 maternal gene MALAT1 as well as its modulation of QKI expression. Our results demonstrated that the secretion of exosomes enriched with hsa-circ-0000326 by YY1-overexpressing M2 macrophages contributes to PCa metastasis. Hsa-circ-0000326 functions as a competitive endogenous RNA against miR-338-3p to promote androgen receptor levels in PCa cells. Mechanistic investigations revealed that YY1 binds to the super-enhancer region of MALAT1 enhancing transcriptional activity for this gene. Simultaneously, YY1 upregulates QKI expression, facilitating splicing events leading to the formation of hsa-circ-0000326. Inhibiting exosomal hsa-circ-0000326 presents a potential therapeutic approach for treating metastatic PCa.

This study evaluates the H2AX/γ-H2AX expression in soft tissue sarcomas (STS), its implications for biological behavior and immune environment, and its potential as a prognostic biomarker. RNA-Seq data from 237 STS were obtained from The Cancer Genome Atlas project. Patients were stratified by H2AX mRNA expression using a survival-associated cutoff. Differentially expressed genes and pathways as well as immune signatures between H2AXhigh- and H2AXlow tumors were identified with DESeq2 analysis, gene set enrichment analyses (GSEA), Enrichr pathway analysis and CIBERSORTx. Tissue microarrays of a different cohort of 291 STS were generated for immunohistochemical staining to assess γ-H2AX protein expression, followed by statistical evaluation. High H2AX mRNA expression was associated with shorter overall survival (OS) in STS (p = 0.02), particularly in leiomyosarcomas (LMS) (p < 0.001), and was a negative prognostic factor in LMS (HR 11.15, p < 0.001). H2AXhigh LMS tumors showed upregulation of cell cycle-related pathways, while H2AXlow LMS exhibited increased inflammatory activity, including elevated M1 macrophage signatures and resting mast cell signatures (both p < 0.001). High γ-H2AX protein levels were an independent negative prognostic factor in the total LMS cohort (HR 12.12, p = 0.025) and in the subgroup of non-uterine LMS (HR 153.80, p = 0.013). Consistent with CIBERSORTx analysis, γ-H2AXlow LMS showed higher mast cell infiltration than γ-H2AXhigh LMS (p = 0.038). In conclusion, H2AX mRNA and γ-H2AX protein expression are associated with distinct biological behavior, differences in the immune cell environment, and might serve as useful prognostic biomarkers in LMS.

Endometrial cancer (EC) is a prevalent gynecologic cancer, with worldwide increasing incidence and disease-associated mortality. N-glycosylation, a critical post-translational modification, has been implicated in cancer progression and immune response modulation. We aimed to elucidate the role of N-glycosylation-related genes on EC cell heterogeneity, prognosis, and immunotherapy response.

Data from single-cell RNA sequencing (scRNA) of five patients with EC were acquired from the Gene Expression Omnibus (GEO) database. Nonnegative matrix factorization (NMF) was used to identify cell subtypes related to N-glycosylation from a scRNA matrix. Subsequently, a consensus prognostic signature by integrating 101 combinations of 10 machine learning algorithms. The response to immunotherapy in EC was further examined by multiple algorithms.

Our findings identified 11,020 differentially expressed genes (DEGs), of which 34 N-glycosylation-related DEGs were remarkably associated with overall survival (OS) in EC. Single-cell RNA sequencing analysis revealed 30,233 cells divided into eight clusters, with T cells and epithelial cells showing distinct functional characteristics. NMF clustering further classified malignant cells into four subtypes: N-glycosylation-C0, Glycosphingolipid-C1, O-GalNAc-C2, and Elongation-C3. The O-GalNAc-C2 subtype exhibited the highest metabolic pathway activity and activation of transcription factors SOX4, JUND, and FOS. Additionally, cell-cell interaction networks highlighted the MK signaling pathway as a critical mediator of intercellular communication. An integrated machine learning framework generated a prognostic model comprising eight DEGs (LAMC2, KRT7, IL32, KRT18, SERPINA1, PGR, AKAP12, EDN2), achieving an average C-index of 0.712 in training and validation cohorts. A low-risk score implies more significant immune cell infiltration and better response to immunotherapy.

Our study underscores the role of N-glycosylation-related genes in EC prognosis and immunotherapy response prediction, and may provide a basis for the development of targeted therapies and personalized treatment strategies.

Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.

Metformin is a traditional antidiabetic drug for type 2 diabetes mellitus. However, it showed antitumor activity in many types of tumors, and it also has an influence on tumor metastasis in several types of tumors. It is transported through organic cationic transporters (OCTs), OCT1, OCT2, and OCT3, into the cells or into tumor microenvironment (TME). The complex interaction of metformin and its transporters on immune infiltration in TME of different types of tumors of The Cancer Genomic Atlas (TCGA) is not yet studied. The objective of this study is to identify the most suitable therapeutic target of tumors and immune infiltrates for metformin and its transporters in the TME. TIMER2.0, a bioinformatic tool, and other computational analysis were used to investigate this complex interaction; moreover, the identification of metformin target protein in TME is also investigated. The results revealed that the most suitable therapeutic target for metformin and OCTs among 32 types of TCGA data tumor types is Breast Invasive carcinoma (BRCA), and the most relevant immune infiltrate among 14 types of immune infiltrates that yields better prognosis and better therapeutical effect in TME is Macrophage M1. Furthermore, metformin showed a cytotoxic effect and an inhibitory effect on Urokinase Plasminogen Activator (uPA) gene expression in a concentration dependent fashion in MDA-MB-231 breast cancer cell line. This may suggest that metformin is a promising antitumor drug, stimulant for natural antitumor immune infiltrates, and inhibitor for metastasis in breast cancer.

The development and progression of nasopharyngeal carcinoma (NPC) involves intricate interactions between tumor cells and other surrounding cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play pivotal roles in the progression of NPC, but their interactions remain largely unexplored. In this study, we revealed that NPC promoted M2-like polarization of TAMs through enhanced synthesis and secretion of WNT2. These M2-type macrophages, in turn, significantly boosted the proliferation and metastasis of NPC. This vicious cycle perpetuated the malignant progression of NPC. Mechanistically, elevated m6A modification of WNT2 in NPC stabilized its mRNA and facilitated its protein expression, which is coordinately regulated by the m6A "eraser" ALKBH5 and the "reader" YTHDF1. NPC promoted M2-like polarization of macrophages by activating the FZD2/β-catenin signaling axis through paracrine WNT2. Furthermore, elevated WNT2 can also trigger the WNT/β-catenin signaling pathway in NPC cells through autocrine signaling, synergically contributing to NPC development. The research reveals that WNT2 is upregulated in an m6A modification-dependent manner and promotes M2-like macrophages polarization of TAMs and malignant progression of NPC. This discovery provides novel potential molecular markers and therapeutic targets for the diagnosis and treatment of NPC.

This study aims to explore the common immune-related gene characteristics of cholangiocarcinoma (CHOL) and inflammatory bowel disease (IBD) to predict disease prognosis. By analyzing the gene expression data from the TCGA, GEO, and NGDC databases, differentially expressed immune-related genes (DE-IRGs) were screened, and a prognostic model was constructed. The results showed that CCR7, OSM, S100P, ACVR1C, OSMR, SPP1, and PIK3R3 were key immune-related genes, and their expressions were closely related to the occurrence and development of CHOL and IBD. Patients in the low immune risk score (IRS) group had more abundant antitumor immune cell infiltration, while those in the high IRS group had more macrophage infiltration. In addition, the model based on these genes had good predictive ability for the diagnosis and prognosis of CHOL and IBD, with an area under the ROC curve (AUC) value exceeding 0.7. This study also predicted potential small molecule drugs that might be effective for the treatment of CHOL, such as Umbralisib and Tamoxifen. In conclusion, this study provides new biomarkers and potential targets for diagnosis, prognosis assessment, and treatment of CHOL and IBD.

Despite advances in immunotherapy, metastatic melanoma remains a considerable therapeutic challenge due to the complexity of the tumor microenvironment. Intratumoral type I interferon (IFN-I) has long been associated with improved clinical outcomes. However, several IFN-I subtypes can also paradoxically promote tumor growth in some contexts. We investigated this further by engineering murine B16 melanoma cells to overexpress various IFN-I subtypes, where a spectrum of outcomes was observed. Characterization of these tumors by RNA sequencing revealed a tumor immune phenotype, where potent IFN-I signaling concomitant with diminished type 2 inflammation failed to confer durable tumor control. T cell-mediated rejection of these tumors was restored by introducing interleukin-4 (IL-4) into the tumor microenvironment, either through ectopic expression or in a preclinical adoptive T cell therapy model. Collectively, our findings highlight the IFN-I/IL-4 axis in promoting antitumor immunity, which could be harnessed to target and stratify solid tumors that are nonresponsive to frontline therapies.

Metal-organic frameworks (MOFs) are crystalline porous materials with tunable structures, where metal ions or clusters serve as magnetic centers and organic ligands offer spatial separation. These characteristics, combined with their diverse topologies, make MOFs promising candidates for contrast agents (CAs) in magnetic resonance imaging (MRI). Herein we synthesized four MOFs based on the same triangular Fe3O clusters with different topologies: MIL-101(Fe) (moo net), MIL-100(Fe) (mtn net), MIL-59(Fe) (pcu net), and MIL-88B(Fe) (acs net). To clarify the relationship between topologies and T2 relaxivities, the MOFs were tailored into uniform, nanoscale spherical morphologies. Notably, the value of T2 relaxivity for MIL-88B(Fe) with acs topology is nearly three times that for MIL-101(Fe) with moo topology at 7.0 T. By comparing the magnetic properties of Fe3O molecular clusters and Ga-doped MIL-88B(Fe), our analysis demonstrated the significant advantage of MOFs with fixed arrays, adjustable components and diverse topologies in enhancing magnetic relaxation. Cellular MRI experiments further revealed that MIL-88B(Fe) could differentiate between M1 and M2 macrophages, highlighting its potential for monitoring tumor progression. These findings offer valuable insights into how MOF topology can be strategically utilized to enhance T2 relaxivities for MRI applications.

Hepatoblastoma (HB), the most common pediatric liver malignancy, is characterized by aggressive growth and metastasis driven by complex angiogenic mechanisms. This review elucidates the pivotal role of angiogenesis in HB progression, emphasizing metabolic reprogramming, tumor microenvironment (TME) dynamics, and oncogenic signalling pathways. The Warburg effect in HB cells fosters a hypoxic microenvironment, stabilizing hypoxia-inducible factor-1α (HIF-1α) and upregulating vascular endothelial growth factor (VEGF), which synergistically enhances angiogenesis. Key pathways such as the Wnt/β-catenin, VEGF, PI3K/AKT, and JAK2/STAT3 pathways are central to endothelial cell proliferation, migration, and vascular maturation, whereas interactions with tumor-associated macrophages (TAMs) and pericytes further remodel the TME to support neovascularization. Long noncoding RNAs and glycolytic enzymes have emerged as critical regulators of angiogenesis, linking metabolic activity with vascular expansion. Anti-angiogenic therapies, including VEGF inhibitors and metabolic pathway-targeting agents, show preclinical promise but face challenges such as resistance and off-target effects. Future directions advocate for dual-target strategies, spatial multiomics technologies to map metabolic-angiogenic crosstalk, and personalized approaches leveraging biomarkers for risk stratification. This synthesis underscores the need for interdisciplinary collaboration to translate mechanistic insights into durable therapies, ultimately improving outcomes for HB patients.

The tumor microenvironment (TME) is characterized by distinct metabolic adaptations that not only drive tumor progression but also profoundly influence immune responses. Among these adaptations, lactate, a key metabolic byproduct of aerobic glycolysis, accumulates in the TME and plays a pivotal role in regulating cellular metabolism and immune cell function. Tumor-associated macrophages (TAMs), known for their remarkable functional plasticity, serve as critical regulators of the immune microenvironment and tumor progression. Lactate modulates TAM polarization by influencing the M1/M2 phenotypic balance through diverse signaling pathways, while simultaneously driving metabolic reprogramming. Furthermore, lactate-mediated histone and protein lactylation reshapes TAM gene expression, reinforcing their immunosuppressive properties. From a therapeutic perspective, targeting lactate metabolism has shown promise in reprogramming TAMs and enhancing anti-tumor immunity. Combining these metabolic interventions with immunotherapies may further augment treatment efficacy. This review underscores the crucial role of lactate in TAM regulation and tumor progression, highlighting its potential as a promising therapeutic target in cancer treatment.

In the presence of cancers, Tumor Associated Macrophages have a well-established role, but the literature provides limited evidence regarding their involvement in the onset and malignant transformation of Oral Potentially Malignant Disorders (OPMDs).

The present systematic review aimed to collect evidence on the presence and characterization of macrophages in the microenvironment of OPMDs.

PubMed, Scopus, EMBASE, Web of Science.

Ex vivo or in silico human studies reporting original quantitative data on macrophage infiltration in OPMDs or Oral Epithelial Dysplasia (OED), published from 1990 onward.

Thirty-seven studies were included for qualitative analysis. Investigated OPMDs included: oral leukoplakia, oral lichen planus, oral lichenoid lesions, proliferative leukoplakia, oral submucous fibrosis, actinic cheilitis, chronic graft vs. host disease.

Even though the heterogeneity of data from the included studies prevents a meta-analysis, the reported results are quite consistent in supporting an increasing macrophage infiltration from normal mucosa to OPMDs, OED, and Oral Squamous Cell Carcinoma (OSCC). An M1 pro-inflammatory polarization is prevalent in OPMDs, with a shift toward an M2 pro-tumorigenic polarization in moderate-severe OED and OSCC. Several novel markers including STAT1, IDO, PD-L1, APOE, ITGB2 appear to be able to identify macrophage clusters involved in pro-inflammatory or pro-tumorigenic pathways.

Evidence from the present review supports an active role of macrophages in regulating immune suppression, oncogenesis, and tumor progression in OPMDs and during the transition to OSCC. Future research should focus not merely on cell quantification and general M1/M2 polarization but rather on the expression of specific markers potentially linked to immunomodulatory pathways involved in oncogenesis.

Ovarian cancer (OC) progression is heavily influenced by the tumor microenvironment (TME), where immune suppression plays a critical role. This study explores the role of thrombospondin-1 (THBS1) in regulating tumor-associated macrophages (TAMs), T cell exhaustion, and immune checkpoint expression, as well as its transcriptional regulation by SNF2H.

We analyzed THBS1 expression and its clinical significance using publicly available datasets (TCGA-OV, GSE14407) and tissue microarrays containing OC and adjacent normal tissues. In vitro functional studies were conducted using OC cell lines (SKOV3, A2780) and co-cultures with macrophages. Chromatin immunoprecipitation (ChIP) assays and RNA interference were employed to investigate SNF2H-mediated transcriptional regulation of THBS1. In vivo, the role of THBS1 in immune suppression was validated using mouse tumor models.

THBS1 was significantly overexpressed in OC tissues and associated with poor prognosis. High levels of THBS1 correlated with increased TAM infiltration, M2 macrophage polarization, and upregulation of immune checkpoints PD-L1 and GAL-3, which contribute to T cell exhaustion. Functional assays demonstrated that THBS1 promotes macrophage recruitment and induces M2 polarization through TGF-β1 and IL-4 signaling. Additionally, ChIP assays identified SNF2H as a transcriptional regulator of THBS1, contributing to its overexpression. In vitro targeting of THBS1 reduced TAM-mediated immune suppression and restored T cell cytotoxicity.

This study positions THBS1 as a key regulator of the OC TME, linking TAM recruitment and polarization to CD8+ T cell exhaustion via immune checkpoint modulation. By identifying SNF2H as a transcriptional regulator of THBS1, we offer new insights into its epigenetic dysregulation and suggest potential therapeutic strategies to reprogram the TME and improve the effectiveness of immunotherapy.

While neoadjuvant chemotherapy combined with surgical resection has improved the prognosis for patients with osteosarcoma, its impact on metastatic and recurrent cases remains limited. Immunotherapy is emerging as a promising alternative. However, the relationship between the phenotype of tumor-associated macrophages and the prognosis of osteosarcoma remains unclear. Differentially expressed gene during macrophage polarization were identified using the Monocle package. Weighted gene co-expression network analysis was conducted to select genes regulating macrophage polarization. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression were used to construct long-term survival predictive strategies. Multiple machine learning algorithms identified target genes for pan-cancer analysis. Lentiviral transfection created stable strains with target gene knockdown, and CCK-8 and transwell migration assays verified the target gene's effects. Western blot and flow cytometry assessed the impact of target genes on macrophage polarization. A total of 141 genes regulating macrophage polarization were identified, from which eight genes were selected to construct prognostic models. Significant differences between high-risk and low-risk groups were observed in immune cell activation, immune-related signaling pathways, and immune function. The prognostic model and target gene were validated to provide more precise immunotherapy options for osteosarcoma and other tumors. BNIP3 knockdown decreased osteosarcoma cell proliferation and migration and promoted macrophage polarization to the M2 phenotype. The constructed prognostic model offers precise immunotherapy regimens and valuable insights into mechanisms underlying current studies. Furthermore, BNIP3 may serve as a potential immunotherapeutic target for osteosarcoma and other tumors.

Lung cancer, a malignant neoplasm that is globally prevalent and characterized by high incidence and mortality rates, has seen the rise of immune checkpoint inhibitors (ICIs) as a crucial systemic treatment. However, a subset of patients exhibits suboptimal responses to ICIs. Recently, studies revealed the role of vitamin D in inflammation modulation, cell differentiation, and cancer prevention. Vitamin D precisely modulates immune responses and inflammatory states within the tumor microenvironment (TME) by targeting both innate and adaptive immunity. These effects may reduce immune tolerance to ICIs and synergistically enhance their therapeutic efficacy. Here, we review vitamin D metabolism in lung cancer patients, as well as its anti-tumor mechanisms, immune regulation, and the significant promise of vitamin D in lung cancer immunotherapy and adjuvant therapeutic strategies. Further research is imperative to surmount these challenges and fully realize vitamin D's potential in improving lung cancer immunotherapy outcomes.

Developing a minimally invasive and potent therapy for nasopharyngeal carcinoma is still challenging. In this study, we report a photothermal nanovaccine based on phenylboronic acid (PBA)-modified poly(amidoamine) dendrimers of generation 5 (G5) attached with indocyanine green (ICG) as a photothermal agent, toyocamycin (Toy) as an endoplasmic reticulum stress (ERS) drug, and Mn2+-coordinated metal-phenolic networks. The developed nanocomplexes are camouflaged with homologous apoptotic cancer cell membranes, leveraging membrane proteins as an antigenic reservoir and incorporating the immune adjuvant cytosine-guanine (CpG) oligonucleotide to obtain the final nanovaccine formulation. The prepared nanovaccine with a size of 72.4 nm displays satisfactory colloidal stability and photothermal conversion efficiency (36.7%), and is capable of targeting cancer cells and inducing apoptosis under laser irradiation through combined ICG-mediated photothermal therapy, Toy-enabled chemotherapy and Mn2+-mediated chemodynamic therapy. Meanwhile, the combined therapeutic effects can elicit immune responses to mature dendritic cells through the immunogenic cell death of cancer cells and the inserted CpG adjuvant/apoptotic cancer cell membranes, and polarize tumor-associated macrophage cells to the antitumor M1 phenotype. The antitumor efficacy of the nanomedicine platform was proven by the test of the penetration and therapeutic inhibition of 3-dimensional tumor spheroids in vitro. The developed functional nanomedicine integrated with different therapeutic modes may be developed as a biomimetic therapeutic nanovaccine for nasopharyngeal carcinoma treatment.

Ferroptosis in the tumor microenvironment (TME) plays a crucial role in the development, metastasis, immune escape, and drug resistance of various types of cancer. A better understanding of ferroptosis in the TME could illuminate novel aspects of this process and promote the development of targeted therapies. Compelling evidence indicates that exosomes are key mediators in regulating the TME. In this respect, it is now understood that exosomes can deliver biologically functional molecules to recipient cells, influencing cancer progression by reprogramming the metabolism of cancer cells and their surrounding stromal cells through ferroptosis. In this review, we focus on the role of exosomes in the TME and describe how they contribute to tumor reprogramming, immunosuppression, and the formation of pre-metastatic niches through ferroptosis. In addition, we highlight exosome-mediated ferroptosis as a potential target for cancer therapy and discuss strategies employing exosomes in ferroptosis treatment. Finally, we outline the current applications and challenges of targeted exosome-mediated ferroptosis therapy in tumor immunotherapy and chemotherapy. Our aim is to advance research on the link between exosomes and ferroptosis in the TME, and we pose questions to guide future studies in this area.

Cancer immunotherapy has transformed malignancy treatment, but the tumor microenvironment (TME) presents significant obstacles. PD-1 blockade therapy, while widely used, faces issues such as resistance, adverse events, and limited predictive biomarkers. Therefore, novel therapeutic strategies are needed to enhance their efficacy and safety. Tumor-associated macrophages (TAMs), often exhibiting an anti-inflammatory M2 phenotype, contribute to poor prognoses and treatment resistance. Targeting TAMs to repolarize them to a pro-inflammatory M1 state can alleviate immunosuppression and enhance T cell-mediated antitumor responses. TMP195, a class IIa histone deacetylase inhibitor, has shown potential in reprogramming TAMs and synergizing with anti-PD-1 antibodies, although clinical application challenges exist. This study aimed to enhance the PD-1 blockade immunotherapy effectiveness by activating tumor-killing macrophages and T cells using biomimetic nanomedicines. A novel macrophage cell membrane-coated PLGA nanoparticle loaded with small molecule inhibitor, TMP195 (M1@PLGA-PEG-TMP195), was designed, prepared, and characterized. This macrophage membrane-coated PLGA nanoparticle delivery system had good drug loading and cancer cell targeting ability. This approach repolarized TAMs to M1 phenotypes and, combined with PD-1 inhibitors, achieved synergistic cancer treatment effects, improving therapeutic efficacy and inhibiting breast cancer growth and metastasis.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy characterized by rapid progression, significantly impacting patients' quality of life. Analyzing gene co-expression modules offers valuable insights into the molecular mechanisms driving ACC progression. In this study, we applied Weighted Gene Co-Expression Network Analysis (WGCNA) to identify gene co-expression modules associated with ACC progression.

Before conducting WGCNA, differential gene expression and immune infiltration analyses were performed on the GSE90713 dataset (available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi ). Dynamic tree cutting was utilized to identify co-expression modules, which were subsequently analyzed to determine their correlations and associations with traits. A total of 21 co-expression modules were identified, with the yellow module demonstrating a strong correlation with the progression of ACC. Enrichment analysis was carried out on differentially expressed genes, the yellow module, cross-module interactions, and the final hub genes to identify the associated Biological Processes (BPs) and pathways relevant to ACC. Additionally, the CIBERSORT algorithm was employed to predict immune cell infiltration in ACC.

The enrichment analysis revealed that pathways associated with cell division, protein synthesis, and metabolism play significant roles in the progression of ACC. Additionally, CDK1, AURKA, CCNB2, BIRC5, CCNB1, TYMS, and TOP2A were identified as key regulatory hub genes. Survival analysis further demonstrated that elevated expression levels of these genes in ACC tissues are significantly correlated with lower overall survival rates in patients, underscoring their critical involvement in ACC development and progression.

This study sheds light on the mechanisms underlying ACC progression and highlights potential therapeutic targets. By identifying specific immune cell subtypes associated with ACC, the findings may aid in developing immune modulation therapies aimed at preventing or treating ACC.

Histone modifications, including methylation, acetylation, lactylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, and crotonylation, critically regulate tumor-associated macrophages (TAMs) polarization by modulating gene expression and functional states. Reprogramming TAMs from M2 to M1 phenotypes through epigenetic targeting has emerged as a promising strategy to enhance anti-tumor immunity and improve the efficacy of cancer immunotherapy. This review explores the role of histone modifications in TAM biology, their interplay with metabolic reprogramming, and the opportunities and challenges in developing epigenetic-based therapies to advance cancer immunotherapy.

Macrophages are heterogeneous cells that are the mediators of tissue homeostasis. These immune cells originated from monocytes and are classified into two basic categories, M1 and M2 macrophages. M1 macrophages exhibit anti-tumorous inflammatory reactions due to the behavior of phagocytosis. M2 macrophages or tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and have a basic role in tumor progression by interacting with other immune cells in TME. By the expression of various cytokines, chemokines, and growth factors, TAMs lead to strengthening tumor cell proliferation, angiogenesis, and suppression of the immune system which further support invasion and metastasis. This review discusses recent and updated mechanisms regarding tumor progression by M2 macrophages. Moreover, the current therapeutic approaches targeting TAMs, their advantages, and limitations are also summarized, and further treatment approaches are outlined along with an elaboration of the tumor regression role of macrophages. This comprehensive review article possibly helps to understand the mechanisms underlying the tumor progression and regression role of macrophages in a comparative way from a basic level to the advanced one.

Recent advances in immunotherapy have spotlighted macrophages as central mediators of disease treatment. Their polarization into pro‑inflammatory (M1) or anti‑inflammatory (M2) states critically influences outcomes in cancer, autoimmunity, and chronic inflammation. Oligonucleotides have emerged as highly specific, scalable, and cost‑effective agents for reprogramming macrophage phenotypes.

To review oligonucleotide strategies-including ASOs, siRNAs, miRNA mimics/inhibitors, and aptamers-for directing macrophage polarization and their therapeutic implications.

We examine key signaling pathways governing M1/M2 phenotypes, describe four classes of oligonucleotides and their mechanisms, and highlight representative preclinical and clinical applications.

Agents such as AZD9150, MRX34, and AS1411 demonstrate macrophage reprogramming in cancer, inflammation, and infection models. Advances in ligand‑conjugated nanoparticles and chemical modifications improve delivery and stability, yet immunogenicity, off‑target effects, and formulation challenges remain significant barriers.

Optimizing delivery platforms, enhancing molecular stability, and rigorous safety profiling are critical. Integration with emerging modalities-such as engineered CAR‑macrophages-will enable precise, disease‑specific interventions, and advance oligonucleotide‑guided macrophage modulation toward clinical translation.

Dysregulated expression of ribosomal protein S3A (RPS3A) is associated with the tissue infiltration of immune-related cells in a variety of cancers. However, the role of RPS3A in immune cell infiltration in glioma remains unclear. This study aimed to explore the role of RPS3A in the glioma immune microenvironment. RPS3A expression was detected in tumor tissues from patients with glioma. U251 cells were transfected with RPS3A shRNA (sh-RPS3A) and overexpression vector (pcDNA-RPS3A) and then co-cultured with PMA-induced THP-1 cells. Cell viability, invasion, and apoptosis were detected by Edu staining, Transwell, and flow cytometry, respectively. The expression of tumor-associated macrophage (TAM) M1 and M2 markers was detected with RT-qPCR. Next, the interaction between RPS3A and E4 transcription factor 1 (E4F1) was verified by Co-IP analysis, and the binding of E4F1 to colony-stimulating factor 1 (CSF1) promoter was verified by ChIP analysis. Overexpression vectors of CSF1 and E4F1 were used to treat sh-RPS3A-transfected U251 cells for reversal experiments. Finally, U251 cells transfected with sh-RPS3A adenovirus vectors were subcutaneously injected into nude mice to construct a xenograft tumor model, and the growth and metastasis of glioma in vivo were monitored. RPS3A was significantly upregulated in glioma tissues. Overexpression of RPS3A promoted glioma cell proliferation and invasion and inhibited apoptosis. Moreover, overexpression of RPS3A promoted TAM proliferation, invasion, and M2 polarization. Silencing RPS3A had the opposite effect. Silencing RPS3A inhibited autophagy in U251 cells, whereas rapamycin, an activator of autophagy, reversed the inhibitory effect of RPS3A silencing on TAM M2 polarization. Meanwhile, RPS3A promoted its expression by interacting with E4F1, and E4F1 promoted CSF1 transcriptional activation. Overexpression of CSF1 promoted the proliferation and invasion of U251 cells and reversed the inhibitory effect of RPS3A silencing on TAM proliferation and invasion, but had no effect on TAM M2 polarization. The results of in vivo experiments showed that knockdown of RPS3A significantly inhibited glioma tumor growth and metastasis in vivo. This study revealed that RPS3A recruited TAMs by upregulating E4F1-mediated transcription activation of CSF1, and promoted the M2 polarization of TAMs through autophagy, promoting glioma cell malignant growth and tumor progression.

Bladder cancer development is closely associated with the dynamic interaction and communication between M2 macrophages and tumor cells. However, specific biomarkers for targeting M2 macrophages in immunotherapy remain limited and require further investigation.

In this study, we identified key co-expressed genes in M2 macrophages and developed gene signatures to predict prognosis and immunotherapy response in patients. Public database provided the bioinformatics data used in the analysis. We created and verified an M2 macrophage-related gene signature in these datasets using Lasso-Cox analysis.

The predictive value and immunological functions of our risk model were examined in bladder cancer patients, and 158 genes were found to be significantly positively correlated with M2 macrophages. Moreover, we identified two molecular subgroups of bladder cancer with markedly different immunological profiles and clinical prognoses. The five key risk genes identified in this model were validated, including CALU, ECM1, LRP1, CYTL1, and CCDC102B, demonstrating the model can accurately predict prognosis and identify unique responses to immunotherapy in patients with bladder cancer.

In summary, we constructed and validated a five-gene signature related to M2 macrophages, which shows strong potential for forecasting bladder cancer prognosis and immunotherapy response.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults and has high mortality rates worldwide. GBM progression, treatment, and prognosis are influenced by the tumor microenvironment (TME), which includes immune, stromal, and tumor cells. Among them, glioblastoma-associated macrophages (GAMs) act as key regulators of GBM pathobiology. GAMs exhibit remarkable plasticity, as they can exhibit both protumor and antitumor effects. However, their function is determined by polarization and the TME. In this review, we provide a comprehensive overview of the current understanding of the biology of GAMs in GBM, including their origins, phenotypic diversity, and functional roles. We discuss the intricate crosstalk between GAMs and tumor cells, as well as other immune and stromal components, and highlight the mechanisms underlying GAM-mediated tumor progression, invasion, angiogenesis, and immune system evasion. Furthermore, we explore the therapeutic implications of targeting GAMs in GBM and discuss emerging strategies aimed at reprogramming GAMs toward an antitumorigenic phenotype or selectively depleting protumorigenic subsets. The final aim is to develop innovative therapeutic approaches that disrupt GBMs. By leveraging our increased understanding of GAM biology, we lay the foundation for transformative advances in GBM treatment to improve patient prognosis.

Acral lentiginous melanoma (ALM) is a rare melanoma subtype primarily located in acral regions. However, ALMs exhibit a distinctive genetic profile characterized by a high number of copy number variations (CNVs) and limited point mutations. Late diagnosis and restricted therapeutic efficacy contribute to its poor prognosis. The secretome within the tumor microenvironment (TME) influences immune modulation and plays a vital role in melanoma progression. We aim to analyze the role of ALM secretome and CNVs profile with prognosis in primary ALM patients. Here, we demonstrated that high CNV burden (CNVsHigh) was associated with worse clinicopathological characteristics and poor prognosis. Furthermore, our study also revealed that conditioned media (CM) of CNVsHigh genetic profile ALM cell line was associated with pro-tumoral, pro-angiogenic, and immunosuppressive secretome profiles. In addition, CM of CNVsHigh cell lines in vitro promotes macrophage polarization to immunosuppressive phenotype. Moreover, we observed an increased presence of immunosuppressive tumor-associated macrophages (TAMs) at the invasive front (IF) of CNVsHigh ALM biopsies. This research reveals the adverse prognostic impact of CNVsHigh in ALM patients, establishing a novel link with a pro-tumor secretome, offering potential biomarkers for prognosis and personalized treatment to enhanced disease monitoring in ALM patients.

Tissue factor pathway inhibitor 2 (TFPI2) is a serine protease inhibitor that suppresses tumors by preventing extracellular matrix degradation and invasion. In many malignancies, the TFPI2 promoter hypermethylation silences its transcription, increasing tumor aggressiveness. However, TFPI2 paradoxically facilitates tumor progression in certain malignancies. Elevated circulating TFPI2 levels correlate with increased cancer aggressiveness and poor prognosis in ovarian, endometrial, and renal cell carcinoma, though the mechanisms underlying its tumor-promoting effects remain unclear. This review consolidates recent findings on TFPI2 regulation, its downstream targets in cellular homeostasis, and its prognostic significance. Additionally, we reassess TFPI2's role in tumorigenesis, particularly in clear cell carcinoma, as well as in chronic inflammation.

A comprehensive literature search was performed in PubMed and Google Scholar without time restriction.

TFPI2 expression is tightly regulated by transcription factors, signaling molecules, growth factors, cytokines, and epigenetic modification. TFPI2 regulates cell proliferation, inflammation, and extracellular matrix (ECM) remodeling, preserving tissue homeostasis. TFPI2 also regulates vascular endothelial and smooth muscle cell proliferation, key elements of the tumor microenvironment (TME). In the nucleus, it may modulate transcription factors to influence tumor-associated macrophage (TAM) polarization, facilitating cancer invasion. Its expression may be shaped by interactions between cancer cells and TAM activation. Beyond tumorigenesis, TFPI2 contributes to both inflammatory progression and resolution in diabetes, atherosclerosis, and preeclampsia.

TFPI2 may interact with TAMs and inflammatory cells to regulate cell proliferation and inflammation, maintaining tissue homeostasis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with complex pathological mechanisms, including immune system dysregulation and chronic inflammation. Recent studies indicate that long non-coding RNAs (LncRNAs) play key roles in immune regulation and have been implicated in the pathogenesis of multiple diseases, including RA and various types of cancer. Understanding the involvement of LncRNAs in RA and their potential transcriptional effects in cancer could provide novel insights into disease mechanisms and therapeutic targets.

Using the GSE94519 dataset, we analyzed serum LncRNA profiles from RA patients and healthy controls. Differential expression genes (DEGs) were identified using GEO2R, and findings were validated via quantitative polymerase chain reaction (qPCR) in 39 RA and 53 healthy samples. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance. A pan-cancer analysis of MTRNR2L1 was conducted using TCGA data, with immune infiltration assessed via ssGSEA.

RNA143598 was significantly upregulated in RA patients, and qPCR confirmed its diagnostic potential (AUC = 0.77). Pan cancer analysis shows that MTRNR2L1 is highly expressed in glioblastoma (GBM) and lowly expressed in head and neck squamous cell carcinoma (HNSC), with high GBM expression linked to poor prognosis. Immune infiltration analysis showed MTRNR2L1 correlated with CD8 + T cells, macrophages, and dendritic cells in GBM.

RNA143598 is a promising RA biomarker, and its transcription gene MTRNR2L1 demonstrates potential in cancer prognosis and immune regulation. These findings provide a foundation for future research on targeted therapies for RA and cancer. Key Points • RNA143598 is identified as a significant biomarker for diagnosing rheumatoid arthritis (RA), showing promise for clinical application. • Quantitative PCR validation demonstrates the diagnostic potential of RNA143598, with an area under the curve (AUC) of 0.77. • MTRNR2L1, which is RNA143598 transcribed gene, exhibits differential expression in different cancer types, with high levels associated with poor prognosis in glioblastoma (GBM). • Immune infiltration analysis links MTRNR2L1 expression to the presence of CD8 + T cells, macrophages, and dendritic cells, suggesting its role in immune regulation in GBM.

Hepatocellular carcinoma (HCC) is a significant global health concern and ranks as the third leading cause of cancer-associated mortality. Systemic therapy faces the emergence of resistance, which hinders the clinical benefits. Recent evidence suggests that exosomes, measuring between 30 and 150 nm in size, which impact the antitumor immune responses, making them a promising candidate for cancer immunotherapy. Owing to their unique physical and chemical characteristics, exosomes can be tailored and engineered for a range of therapeutic objectives. In the present review, we outline the immunomodulatory functions of exosomes in the tumor microenvironment (TME) of HCC, aiming to decipher the underlying mechanisms of exosomes in remodeling suppressive TME. Moreover, we provide detailed and intuitive resource for leveraging the potential of exosomes in immunotherapy, presenting valuable strategies to improve and optimize HCC treatment. Despite the huge therapeutic potential of exosomes, significant challenges persist, including the need for standardization in exosome production, optimization of cargo loading techniques, and the assurance of safety and effectiveness in clinical applications. Addressing these challenges may pave the way for exosome-based immunotherapy for HCC patients.

Breast cancer (BC) is the second leading cause of death among women worldwide. Immunotherapy has become an effective treatment for BC patients due to the rapid development of medical technology. Considerable breakthroughs have been made in research, marking the beginning of a new era in cancer treatment. Among them, various cancer immunotherapies such as immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer are effective and have good prospects. The tumor microenvironment (TME) plays a crucial role in determining the outcomes of tumor immunotherapy. Tumor-associated macrophages (TAMs) are a key component of the TME, with an immunomodulatory effect closely related to the immune evasion of tumor cells, thereby affecting malignant progression. TAMs also significantly affect the therapeutic effect of ICIs (such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors). TAMs are composed of multiple heterogeneous subpopulations, including M1 phenotypes macrophages (M1) and M2 phenotypes macrophages (M2). Furthermore, they mainly play an M2-like role and moderate a variety of harmful consequences such as angiogenesis, immunosuppression, and metastasis. Therefore, TAMs have become a key area of focus in the development of tumor therapies. However, several tumor immunotherapy studies demonstrated that ICIs are effective only in a small number of solid cancers, and tumor immunotherapy still faces relevant challenges in the treatment of solid tumors. This review explores the role of TAMs in BC immunotherapy, summarizing their involvement in BC development. It also explains the classification and functions of TAMs, outlines current tumor immunotherapy approaches and combination therapies, and discusses the challenges and potential strategies for TAMs in immuno-oncology treatments.

Chimeric antigen receptor (CAR) therapy has successfully treated relapsed/refractory hematological cancers. This strategy can effectively target tumor cells. However, despite positive outcomes in clinical applications, challenges remain to overcome. These hurdles pertain to the production of the drugs, solid tumor resistance, and side effects related to the treatment. Some cases have been missed during the drug preparation due to manufacturing issues, prolonged production times, and high costs. These challenges mainly arise from the in vitro manufacturing process, so reevaluating this process could minimize the number of missed patients. The immune cells are traditionally collected and sent to the laboratory; after several steps, the cells are modified to express the CAR gene before being injected back into the patient's body. During the in vivo method, the CAR gene is introduced to the immune cells inside the body. This allows for treatment to begin sooner, avoiding potential failures in drug preparation and the associated high costs. In this review, we will elaborate on the production and treatment process using in vivo CAR, examine the benefits and challenges of this approach, and ultimately present the available solutions for incorporating this treatment into clinical practice.

Ovarian cancer (OC) remains the most lethal gynecological malignancy, primarily due to its late-stage diagnosis, frequent recurrence, and resistance to conventional chemotherapy. A critical factor contributing to OC's aggressiveness is the tumor microenvironment (TME), particularly the presence and polarization of tumor-associated macrophages (TAMs). TAMs, often skewed toward an immunosuppressive M2-like phenotype, facilitate tumor growth, angiogenesis, metastasis, and resistance to therapy. This comprehensive review delves into the multifaceted regulation of macrophage polarization in OC, highlighting key molecular pathways such as PTEN loss, Wnt/β-catenin signaling, NF-κB, Myc, STAT3, and JNK, among others. Additionally, it explores the role of chemokines, non-coding RNAs, and various proteins in modulating TAM phenotypes. Emerging evidence underscores the significance of extracellular vesicles (EVs) and ovarian cancer stem cells (CSCs) in promoting M2 polarization, thereby enhancing tumor progression and therapy resistance. The review also identifies critical biomarkers associated with macrophage polarization, including CD163, LILRB1, MUC2, and others, which hold prognostic and therapeutic potential. Therapeutic strategies targeting TAMs are extensively discussed, encompassing oncolytic viruses, engineered EVs, immunotherapies, nanoparticles, targeted therapies, and natural products. These approaches aim to reprogram TAMs from a pro-tumorigenic M2 state to an anti-tumorigenic M1 phenotype, thereby enhancing immune responses and overcoming resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Furthermore, the review addresses the interplay between macrophage polarization and therapy resistance, emphasizing the need for novel interventions to modulate the TME effectively. By synthesizing current knowledge on macrophage polarization in ovarian cancer, this study underscores the potential of targeting TAMs to improve clinical outcomes and personalize treatment strategies for OC patients. Continued research in this domain is essential to develop robust therapeutic frameworks that can mitigate the immunosuppressive TME and enhance the efficacy of existing and novel cancer therapies.

In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a "cold" tumor into a "hot" tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.

Macrophages, polarized into pro-inflammatory M1 or anti-inflammatory M2 states, are essential cellular elements of innate immunity. In the tumor microenvironment, owing to a paracrine manipulative program by cancerous cells, tumor-associated macrophages (TAMs) evolve, which can shift between M1-like and M2-like phenotypes. Since it is fairly unknown how the promising anticancer agents, silver (AgNPs) and gold nanoparticles (AuNPs) affect the bidirectional communication and reprogramming in the tumor stroma, we examined the behavior, the tumor-supporting functions, and the expression of polarization and functional marker genes of TAMs to reveal how these are modulated upon interaction with nanoparticle-exposed cancer cells.

We established co-cultures of murine immortalized J774 or primary bone marrow-derived macrophages with 4T1 breast cancer cells treated with AuNPs or AgNPs or with none of the nanoparticles. We assessed the expression of macrophage polarization and functional markers using RT-qPCR and Proteome Profiler Array and evaluated macrophage migration and matrix metalloproteinase activity by specific assays.

Protein and mRNA levels of most examined factors - except tumor necrosis factor-alpha - such as C-C-motif chemokine ligands 2 and 22, interleukin-23, inducible nitric oxide synthase, cyclooxygenase-2, the macrophage mannose receptor CD206, transforming growth factor-beta, and chitinase-like-3 protein decreased, and the expression of polarization markers revealed a shift towards M1-like phenotype in macrophages co-cultured with AgNP- or AuNP-treated 4T1 cells. Both nanoparticle treatments reduced the levels and activity of cell migration-related factors, such as C-C motif chemokine ligand 3, matrix metalloproteinases, and suppressed macrophage migration.

Both AuNPs and AgNPs showed a remarkable ability to influence macrophage-cancer cell communication, suppressed indirectly M2-like TAM polarization, and perturbed the migration behavior of TAMs that is critical for tumor invasion, indicating modulated immunological functions and debilitated cancer-promoting capabilities of TAMs in this microenvironment.

Background/Objectives: Peripheral neuroblastic tumors (pNT) are a biologically heterogeneous group of embryonal tumors that derive from the neural crest and affect the sympathetic nervous system. So far, little is known about the complex immune landscape in these rare childhood cancers. Methods: We focused on the immune cell infiltrate of treatment-naïve pNT from 24 patients, including high-risk neuroblastoma (HR-NBL), non-high-risk neuroblastoma (NHR-NBL), ganglioneuroblastoma (GNBL), and rare ganglioneuroma (GN). To gain novel insights into the immune architecture of these pNT subtypes, we used multiplex immunohistochemistry, multispectral imaging, and algorithm-based data evaluation to detect and characterize T cells, B cells, neutrophils, macrophages, and tertiary lymphoid structures (TLS). Results: The majority of the investigated tumor-infiltrating immune cells were macrophages and T cells. Their detailed phenotypic characterization revealed high proportions of M2-like macrophages as well as activated GrzB+ CD8+ and PD-1+ T lymphocytes. Proportions of these T cell phenotypes were significantly increased in GN compared to HR-NBL, NHR-NBL, or GNBL. In addition, TLS occurred in 11 of 24 patients, independent of immune cell frequencies in the whole tissues. Interestingly, all GN, most GNBL, but only a few NBL contained TLS. We distinguished between three TLS maturation stages that were present irrespective of the pNT subtype. The majority belonged to mature TLS of the primary follicle state. Mature LAMP3+ dendritic cells were also found, predominantly in T cell zones of TLS. Furthermore, TLS presence identified pNT patients with significantly prolonged progression-free survival in contrast to all other analyzed immunological features. Conclusions: We propose TLS to be a potential prognostic marker for pNT to predict patient outcomes.

Colorectal cancer (CRC) stands as one of the tumors with globally high incidence and mortality rates. In recent years, researchers have extensively explored the role of the tumor immune microenvironment (TME) in CRC, highlighting the crucial influence of immune cell populations in driving tumor progression and shaping therapeutic outcomes. The TME encompasses an array of cellular and noncellular constituents, spanning tumor cells, immune cells, myeloid cells, and tumor-associated fibroblasts, among others. However, the cellular composition within the TME is highly dynamic, evolving throughout different stages of tumor progression. These shifts in cell subpopulation proportions lead to a gradual transition in the immune response, shifting from an early antitumor growth to a late-stage environment that supports tumor survival. Therefore, it is crucial to further investigate and understand the complex interactions among the various cell populations within the TME. In this review, we explore the key cellular components of varying origins, subpopulations with shared origins, and noncellular elements within the CRC TME, examining their interconnections and critical considerations for developing personalized and precise immunotherapy strategies.