Macrophages are essential components of the innate immune system and play central roles in maintaining immune homeostasis, regulating inflammatory responses, and driving the initiation and progression of a wide range of diseases (Xia et al., 2020). Beyond their classical functions in pathogen clearance and antigen presentation, macrophages exhibit remarkable functional plasticity in response to microenvironmental cues (Xia et al., 2020). In settings such as infection, tissue injury, and the tumor microenvironment, macrophages can adopt distinct activation states that either amplify inflammation or promote immunosuppression, thereby profoundly influencing disease progression and therapeutic outcomes (Yu et al., 2023). Consequently, elucidating the molecular mechanisms that govern macrophage functional regulation is of fundamental importance for understanding immune response modulation and for developing novel therapeutic strategies (Yu et al., 2023). Recent studies have revealed that immune cell fate determination is not solely dictated by transcriptional regulation; post-transcriptional regulation is equally indispensable in shaping immune cell identity and function (Yu et al., 2023). Processes such as mRNA splicing, stability, subcellular localization, and translational efficiency enable rapid and fine-tuned modulation of protein expression programs, allowing immune cells to respond swiftly to dynamic and complex microenvironments (Li et al., 2023). Compared with transcriptional control, post-transcriptional regulation is characterized by faster kinetics and greater reversibility, making it particularly well suited for regulating the dynamic functional states of immune cells (Li et al., 2023). Post-transcriptional regulation, including RBPs and RNA modifications, plays a crucial role in controlling gene expression in immune cells, particularly macrophages. Macrophages are highly plastic and can adopt diverse functional states in response to environmental cues, which is critical in the context of various diseases such as chronic inflammation, cancer, and atherosclerosis. Dysregulation of RBPs or RNA modifications can alter macrophage polarization and function, thereby influencing disease progression (Fernandez et al., 2022). Understanding these regulatory mechanisms not only provides fundamental insights into macrophage biology but also highlights potential therapeutic strategies, including targeted modulation of RBPs or RNA modifications, for treating inflammatory and immune-related diseases (Teixeira-Coelho et al., 2014).

RBPs are central mediators of post-transcriptional gene regulation. By recognizing and binding specific RNA sequences or structural motifs, RBPs regulate RNA splicing, modification, stability, transport, and translation (Finan et al., 2023). The functional specificity of RBPs is determined by their RNA-binding domains (RBDs), which confer both affinity and selectivity for RNA targets (Finan et al., 2023). To date, more than 30 distinct types of RBDs have been identified, among which RNA recognition motifs (RRMs), KH domains, helicase domains, and intrinsically disordered regions (IDRs) are the most common (Qin et al., 2020). RRMs and KH domains typically mediate highly selective binding through recognition of specific nucleotide sequences, whereas helicase domains bind RNA backbones in an ATP-dependent manner to remodel RNA secondary structures (Qin et al., 2020). In contrast, IDRs lack a fixed three-dimensional structure but enhance binding versatility through flexible, multivalent interactions. The combinatorial and cooperative actions of distinct RBDs enable RBPs to precisely control RNA processing, stability, translation, and subcellular localization, thereby exerting broad regulatory influence over gene expression networks (Qin et al., 2020).

Recent studies have highlighted the dynamic interplay between tumor cells and the immune microenvironment as a critical determinant of cancer progression and therapeutic response (Ke et al., 2025; Zhang et al., 2025). For example, iMRS enables personalized prediction of immunotherapy response and prognosis in LUAD, where high iMRS—driven by the immune-exclusion–related oncogene SLC25A1—defines immune-cold tumors with poor outcomes, while targeting SLC25A1 enhances CD8⁺ T cell–mediated immunity and improves anti–PD-1 efficacy (Zhang et al., 2025). In particular, macrophage-driven remodeling of the tumor microenvironment (TME) has emerged as a key mechanism underlying immunosuppressive states, metabolic adaptation, and resistance to immunotherapy (Gong et al., 2025). Growing evidence indicates that post-transcriptional regulatory programs, including those orchestrated by RBPs, are central to shaping macrophage phenotypes and their functional plasticity within the TME, thereby influencing antitumor immunity and treatment outcomes (Gong et al., 2025). EGFR-mutant LUAD exhibits an immunosuppressive tumor immune microenvironment characterized by TIGIT⁺ regulatory T cells, neutrophils, and macrophages, whereas EGFR wild-type tumors display an immune-active TIME with ZNF683⁺ CD8⁺ tissue-resident memory T cells, diverse memory B cells, and FGFBP2⁺ CD16^high NK cells, highlighting distinct immune landscapes that can guide precision immunotherapy (Gong et al., 2025).

Through the assembly of intricate RNA–protein regulatory networks, RBPs serve as pivotal hubs in maintaining cellular homeostasis and coordinating stress responses (Qin et al., 2020). Increasing evidence highlights the critical roles of RBPs in immune cells, particularly macrophages. In macrophages, RBPs regulate the expression of inflammatory mediators, growth factors, and metabolic genes, thereby influencing macrophage polarization, survival and programmed cell death, as well as metabolic reprogramming (Chen et al., 2021). These regulatory processes determine macrophage functional orientation in both acute and chronic inflammation and play crucial roles in cancer, infectious diseases, and metabolic disorders. However, a systematic understanding of RBPs in macrophage biology remains limited, and their integrated roles within immune regulatory networks have not yet been fully elucidated. Therefore, this review aims to comprehensively summarize the roles of RBPs in regulating macrophage polarization, survival and programmed cell death, metabolic reprogramming, and disease progression, with a particular focus on their functional significance in tumor immunity and inflammatory diseases. Furthermore, we explore the potential of RBPs as emerging immunotherapeutic targets. By integrating current research advances, this review seeks to provide a theoretical framework for understanding post-transcriptional regulation in macrophages and for developing novel immunotherapeutic strategies.

Collectively, RBPs orchestrate a highly dynamic and finely tuned gene expression regulatory network by acting across multiple layers, including transcription, RNA splicing, nucleocytoplasmic transport, RNA stability and decay, translational control, RNA epigenetic modification, liquid-liquid phase separation, and chromatin state regulation (Zhu W. et al., 2025). RBPs not only serve as core regulators of post-transcriptional processes but also intersect functionally with chromatin and transcriptional machinery, enabling integrated control over the entire gene expression continuum (Zhu W. et al., 2025). This multilayered and spatiotemporally specific regulatory capacity positions RBPs as critical molecular hubs linking transcriptional programs to protein output. Their functional plasticity provides the molecular basis for rapid cellular adaptation to environmental changes and offers important insights into disease mechanisms and therapeutic development (Figure 1).

While the diverse functions of RNA-binding proteins have been broadly characterized, their cell type–specific regulatory roles in shaping macrophage phenotypes remain incompletely understood. Given that macrophage polarization represents a central determinant of immune responses and tissue homeostasis, the following section focuses on the molecular mechanisms by which RBPs orchestrate macrophage polarization through multilayered post-transcriptional regulation.

Macrophage survival and programmed cell death play central roles in the maintenance of tissue homeostasis, regulation of inflammation, and orchestration of immune responses (Bo et al., 2023). RBPs exert fine-tuned control over macrophage fate through post-transcriptional regulatory mechanisms by modulating the expression of mRNAs associated with cell survival, apoptosis, and other forms of programmed cell death (Lu et al., 2020). RBPs can directly interact with mRNAs encoding pro- or anti-apoptotic factors, including members of the Bcl-2 family, caspases, and components of the TNF-α signaling pathway. By regulating the stability and translational efficiency of these transcripts, RBPs enable rapid amplification or attenuation of apoptotic responses in macrophages. For instance, tristetraprolin (TTP) promotes the degradation of TNF-α mRNA, thereby indirectly reducing the accumulation of pro-apoptotic signals and protecting macrophage survival during the resolution phase of inflammation (Zhang et al., 2020). In contrast, HuR (ELAVL1) stabilizes anti-apoptotic mRNAs, enhances cellular stress tolerance, and sustains immune effector functions. Beyond classical apoptosis, macrophages also undergo alternative forms of programmed cell death, including pyroptosis, ferroptosis, and autophagy-associated cell death, all of which contribute to immune regulation (Zhang et al., 2022a). RBPs participate in these processes by controlling the expression of inflammasome-related genes (such as NLRP3 and IL-1β) and mRNAs involved in iron metabolism, thereby influencing the activation threshold and intensity of these cell death pathways. For example, specific RBPs can stabilize or promote the degradation of NLRP3 mRNA, modulating the magnitude of pyroptosis and shaping the scope and severity of inflammatory responses. In colorectal cancer, high expression of RBP-Jκ promotes the secretion of CXCL11, which activates TGF-β1 expression in TAMs, thereby enhancing cancer cell migration, invasion, and EMT (Liu et al., 2021). This positive feedback loop accelerates metastatic progression, and both RBP-Jκ expression and TAM infiltration serve as independent predictors of metastasis and prognosis in colorectal cancer. In sepsis-associated acute lung injury, macrophages release extracellular vesicles enriched in GBP2 and concurrently undergo ferroptosis, which promotes GPX4 ubiquitination and ferroptosis in endothelial cells, ultimately exacerbating lung injury (Li Z. et al., 2025). Targeting the GBP2–OTUD5–GPX4 axis represents a potential therapeutic strategy in this context. In hepatocellular carcinoma (HCC), FOXM1 upregulates IGF2BP3, which stabilizes RRM2 mRNA in an m⁶A-dependent manner, suppressing ferroptosis in tumor cells while promoting malignant behaviors and M2 macrophage polarization (Gao et al., 2025). These findings suggest that targeting the FOXM1/IGF2BP3/RRM2 axis to enhance ferroptosis may provide therapeutic benefit in HCC (Gao et al., 2025). Additionally, lactate has been shown to transcriptionally upregulate IGF2BP2 through H3K18 lactylation (Zhu J. F. et al., 2025). IGF2BP2 binds to and stabilizes Nrf2 mRNA, thereby enhancing ferroptosis resistance in colorectal cancer cells while simultaneously driving M2 macrophage polarization (Zhu J. F. et al., 2025). This dual effect establishes an immunosuppressive tumor microenvironment that promotes tumor growth and metastasis. Collectively, these studies highlight RBPs as critical regulators linking macrophage survival, diverse forms of programmed cell death, and tumor-associated immune modulation.

Macrophage survival and cell fate decisions are tightly coupled to intracellular metabolic states and energy availability. Accordingly, RBPs-mediated control of RNA metabolism extends beyond cell death regulation to the fine-tuning of metabolic reprogramming, which underlies macrophage activation, functional specialization, and environmental adaptation. Macrophage function is not only governed by signaling pathways and transcription factors but is also highly dependent on cellular metabolic states (Xu R. et al., 2024). The emergence of the concept of immunometabolism has revealed a close interplay between metabolic pathways and immune effector functions (Xu R. et al., 2024). Macrophages dynamically adjust their metabolic programs-such as glycolysis, oxidative phosphorylation (OXPHOS), and lipid metabolism—to support polarization states and functional demands (Xu R. et al., 2024). Pro-inflammatory M1 macrophages exhibit markedly enhanced glycolysis and preferentially engage in aerobic glycolysis (the Warburg effect), even under normoxic conditions, to rapidly generate ATP and metabolic intermediates required for the synthesis of inflammatory mediators and reactive oxygen species (Schwartz et al., 2017). In parallel, the tricarboxylic acid (TCA) cycle is partially disrupted, leading to the accumulation of metabolites such as citrate and succinate, which further reinforce inflammatory signaling and phenotype maintenance (Wu and Minteer, 2019). In contrast, anti-inflammatory and tissue-repair-associated M2 macrophages predominantly rely on oxidative phosphorylation and fatty acid oxidation (FAO) to provide sustained energy supply, supporting anti-inflammatory cytokine production and tissue repair functions (Wu and Minteer, 2019). Enhanced lipid metabolism not only fulfills energetic demands but also contributes to the generation of signaling molecules, such as prostaglandins and lipoxins, which further promote immunosuppressive and reparative responses (Wu and Minteer, 2019). RBPs play a pivotal role in macrophage metabolic reprogramming by regulating the stability and translation of mRNAs encoding metabolic enzymes. Through post-transcriptional control of glycolytic enzymes, mitochondrial respiratory chain components, and lipid metabolism-associated proteins, RBPs influence metabolic pathway selection and indirectly shape macrophage polarization and inflammatory intensity (Sun et al., 2024). This layer of regulation tightly couples metabolic remodeling with functional phenotypes, enabling macrophages to rapidly adapt energy production and immune functions in response to microenvironmental cues (Chen et al., 2025b).

Recent studies have shown that tetrameric pyruvate kinase M2 (PKM2) in macrophages drives glycolytic ATP production, which is subsequently converted extracellularly into adenosine to activate A2a receptors (Palsson-McDermott et al., 2015). This signaling cascade enhances IL-10 secretion and improves mitochondrial function, revealing a PKM2-driven metabolic reprogramming mechanism that promotes anti-inflammatory responses (Palsson-McDermott et al., 2015). In another context, the E3 ubiquitin ligase RNF128 interacts with SRB1 and promotes its Lys63-linked polyubiquitination, enhancing SRB1 membrane recycling and oxidized low-density lipoprotein uptake (Liu Y. et al., 2025). This process induces foam cell formation and inflammatory responses, underscoring the critical role of RNF128-mediated lipid metabolic regulation in atherosclerosis (Liu Y. et al., 2025). Furthermore, in prostate cancer, the histone methyltransferase ASH1L remodels histone methylation patterns in cooperation with HIF-1α, inducing a pro-metastatic transcriptional program in bone metastatic tumor cells (Meng et al., 2025). This reprogramming drives monocyte differentiation toward lipid-associated tumor-associated macrophages (LA-TAMs) and enhances their pro-tumorigenic phenotype, highlighting ASH1L as a key regulator of macrophage metabolic plasticity in bone metastasis and a potential therapeutic target (Meng et al., 2025). In inflammatory arthritis, Pim2 is upregulated in macrophages from patients and mouse models, where it promotes glycolytic reprogramming and M1 polarization by phosphorylating PGK1, PDHA1, and PFKFB2, thereby accelerating disease progression (Xu et al., 2025). Pharmacological inhibition of Pim2 using agents such as HJ-PI01 or neutrophil membrane-coated Bex-PLGA nanoparticles suppresses glycolysis and M1 polarization, alleviating inflammatory arthritis and providing a novel strategy for targeted therapy (Xu et al., 2025). The cumulative effects of RBP-driven regulation of macrophage polarization, survival, and metabolic reprogramming ultimately manifest at the organismal level, contributing to the initiation and progression of diverse diseases. In the final section, we integrate these mechanistic insights to discuss the roles of RBPs in macrophage-associated pathological conditions, including inflammatory disorders, cancer, and metabolic diseases.

RBPs play critical roles in the initiation and progression of a wide range of diseases by regulating macrophage polarization, survival, and metabolic states (Huntington and Gray, 2018). Aberrant expression or functional dysregulation of RBPs can disrupt immune homeostasis, leading to imbalanced immune responses that contribute to the pathogenesis of inflammatory diseases, cancer, infectious disorders, and metabolic diseases (Huntington and Gray, 2018). In inflammatory and autoimmune diseases, dysregulated post-transcriptional control of pro-inflammatory and anti-inflammatory cytokine mRNAs by RBPs often results in the persistent activation of chronic inflammation (Huntington and Gray, 2018). For example, loss or functional impairment of tristetraprolin enhances the stability of TNF-α mRNA, thereby driving sustained inflammatory responses (Huntington and Gray, 2018). In contrast, excessive activation of HuR may promote the expression of anti-inflammatory factors, disturbing immune equilibrium. Mechanistically, HuR binds to AU-rich elements in the 3′untranslated regions of target mRNAs, stabilizing transcripts that encode anti-inflammatory cytokines and regulatory molecules. When HuR activity is abnormally elevated, this can lead to an overrepresentation of anti-inflammatory signals, suppressing normal immune activation and impairing pathogen clearance (Huntington and Gray, 2018). Such an imbalance in cytokine production and immune cell activity may contribute to the development of pathological conditions, including autoimmune diseases, where inappropriate immune suppression or dysregulated tolerance disrupts tissue homeostasis. By linking HuR-mediated post-transcriptional regulation to immune equilibrium, this pathway highlights how dysregulation of RBPs can have direct consequences for disease pathogenesis (Huntington and Gray, 2018). Inflammatory cytokines have been shown to induce the expression of RBM43, which suppresses the translation of PGC1α mRNA, leading to reduced mitochondrial biogenesis and oxidative metabolism (Dumesic et al., 2025). This impairment subsequently disrupts energy metabolism and thermogenic capacity in adipocytes. Adipocyte-specific deletion of Rbm43 enhances PGC1α translation, restores oxidative metabolism, improves glucose tolerance, alleviates adipose tissue inflammation, and suppresses cGAS–STING–mediated immune activation (Dumesic et al., 2025). These findings reveal a critical inflammation–RBM43–PGC1α axis in the pathogenesis of obesity-associated metabolic diseases. RBPMS plays a pivotal role in the phenotypic regulation of vascular smooth muscle cells (VSMCs). By binding to myocardin (MYOCD) pre-mRNA, RBPMS modulates alternative splicing to maintain a balanced ratio of MYOCD_v3 to MYOCD_v1 isoforms, thereby promoting contractile differentiation of VSMCs while suppressing fibrotic activity (Imamura et al., 2010). Consequently, RBPMS reduces fibrous cap formation in atherosclerotic plaques and attenuates neointimal hyperplasia following vascular interventions, highlighting its potential therapeutic value in preventing vascular remodeling and restenosis. DRAK2 has emerged as a key regulator in nonalcoholic steatohepatitis (NASH). DRAK2 expression is markedly elevated in the livers of patients and experimental models with nonalcoholic fatty liver disease (NAFLD) and NASH (Li et al., 2021). Mechanistically, DRAK2 interacts with the splicing factor SRSF6 and inhibits its phosphorylation by SRPK1, thereby modulating alternative splicing of genes involved in mitochondrial function (Li et al., 2021). Liver-specific deletion of DRAK2 effectively suppresses the progression from fatty liver to NASH, indicating that DRAK2 represents a potential therapeutic target for NAFLD/NASH (Li et al., 2021). The secreted micropeptide Cf48 promotes renal interstitial fibrosis in chronic kidney disease (CKD). Cf48 is upregulated in renal tubular epithelial cells in CKD, and its serum levels are positively correlated with renal function decline, CKD stage, and the extent of active fibrosis. Cf48 binds to mRNAs of fibrosis-related genes, such as Serpine1, prolonging their mRNA half-lives and enhancing TGF-β1–mediated fibrotic responses, ultimately promoting extracellular matrix deposition (Li et al., 2025b). Genetic deletion or pharmacological inhibition of Cf48 significantly attenuates renal fibrosis in CKD models, suggesting that Cf48 is a promising therapeutic target (Hu et al., 2023).

Ac⁴C is an evolutionarily conserved RNA modification found on tRNAs, rRNAs, and mRNAs, catalyzed primarily by the acetyltransferase NAT10. Recent studies indicate that ac⁴C can enhance RNA stability and translation efficiency (Chen et al., 2023). In macrophages, ac⁴C modification of specific transcripts may fine-tune the expression of genes involved in inflammatory responses and immune signaling. In patients with atherosclerosis (AS), NAT10 expression is elevated and is accompanied by increased levels of ac4C RNA modification. NAT10 regulates macrophage polarization by catalyzing ac4C modification of TLR9 mRNA. Knockdown of NAT10 promotes the transition from M1 to M2 macrophages, suppresses inflammatory responses, and alleviates AS progression, whereas TLR9 overexpression reverses these effects. These findings suggest that the NAT10–ac⁴C–TLR9 axis plays a crucial role in the development and progression of atherosclerosis. Mechanistically, NAT10 catalyzes ac⁴C modification of specific mRNAs in macrophages, enhancing their stability and translation. This modification promotes the expression of TLR9, a key innate immune receptor, thereby skewing macrophages toward a pro-inflammatory (M1-like) phenotype (Yin et al., 2025). The resulting pro-inflammatory macrophages contribute to lipid accumulation, foam cell formation, and vascular inflammation (Yin et al., 2025), all of which drive plaque development and progression. By linking RNA modification to macrophage polarization, this pathway provides a mechanistic explanation for how post-transcriptional regulation can influence atherosclerotic disease progression and highlights potential targets for therapeutic intervention (Yin et al., 2025). Within the tumor microenvironment, TAMs typically exhibit an immunosuppressive M2-like phenotype that supports tumor growth, angiogenesis, and immune evasion. RBPs in TAMs enhance immunosuppressive functions by stabilizing mRNAs encoding VEGF, IL-10, and TGF-β, and by regulating the expression of metabolism-related genes to sustain energy metabolism and phenotypic characteristics. Through these mechanisms, RBPs not only promote tumor progression but also represent potential targets for therapeutic strategies aimed at reprogramming TAMs (Yin et al., 2025). During pathogen infection, RBPs participate in the regulation of macrophage antimicrobial responses by controlling the expression of inflammatory mediators and antimicrobial factors. For instance, HuR enhances the stability of specific interferon-related mRNAs, thereby improving antiviral response efficiency. Meanwhile, the roles of RBPs in metabolic diseases have also gained increasing attention. In obesity and atherosclerosis, RBPs regulate the expression of genes involved in lipid metabolism, influencing macrophage inflammatory activity and foam cell formation, and thereby contributing to disease initiation and progression (Yin et al., 2025). In summary, RBPs exert fine-tuned control over macrophage functions and play indispensable roles across a broad spectrum of diseases. Their dysregulation can lead to excessive inflammation, immune suppression, or metabolic disturbances, positioning RBPs as promising therapeutic targets for the treatment of macrophage-related pathological conditions.

NSUN5 promotes m5C modification of CTNNB1 chromatin-associated RNA, which is oxidized by TET2 and recognized by RBFOX2, leading to β-catenin mRNA degradation and enhanced TAM-mediated phagocytosis of glioma cells (Wu et al., 2024). Targeting NSUN5, alone or combined with IDH1-R132H or CD47/SIRPα inhibition, potentiates TAM activity and suppresses glioma growth in vivo (Wu et al., 2024).

Owing to their central roles in macrophage functional regulation, RBPs have increasingly emerged as promising targets in immunotherapy research. Unlike classical transcription factors, RBPs primarily exert regulatory control at the post-transcriptional level by modulating RNA splicing, stability, subcellular localization, and translational efficiency. This mode of regulation confers RBPs unique and irreplaceable advantages in shaping immune cell fate decisions and functional programs. From a drug development perspective, RBPs often contain well-defined RNA-binding domains or protein–protein interaction interfaces, rendering them more “druggable” than transcription factors and amenable to selective intervention using small molecules or nucleic acid–based therapeutics.

The therapeutic potential of targeting RNA-binding proteins (RBPs) has gained increasing attention in recent years. Several strategies have been explored, including RNA interference approaches such as siRNA or shRNA, antisense oligonucleotides (ASOs), and small-molecule modulators that directly inhibit RBP activity or disrupt their interactions with target RNAs (Cantara et al., 2024). Despite these promising approaches, significant challenges remain for clinical translation, including achieving cell-type-specific delivery, ensuring in vivo stability, minimizing off-target effects, and overcoming potential toxicity. Integrating RBP-targeted therapies with existing immunotherapy regimens may further enhance clinical efficacy (Crooke et al., 2021). For example, modulating RBPs that regulate macrophage polarization could improve the tumor immune microenvironment, potentially increasing the responsiveness to immune checkpoint inhibitors or other immune-based therapies (Yu and Yao, 2024). Collectively, these insights highlight both the opportunities and the challenges of RBP-targeted interventions, underscoring their potential as a novel class of immunomodulatory therapeutics.

Importantly, RBPs frequently integrate inflammatory signaling, metabolic reprogramming, and cell survival pathways, thereby functioning as network-level regulators. Targeting RBPs therefore offers the possibility of simultaneously modulating macrophage polarization states, metabolic features, and functional homeostasis through a single intervention, providing novel entry points for immunotherapeutic strategies. Current approaches to targeting RBPs include small-molecule inhibitors, RNA interference technologies (siRNA/shRNA), and antisense oligonucleotides (ASOs), which enable precise regulation of pro- or anti-inflammatory gene expression programs. Notably, RBP-targeted strategies exhibit strong potential for synergistic effects with immune checkpoint blockade therapies, such as PD-1/PD-L1 inhibitors. By reshaping the immunosuppressive phenotype of macrophages within the TME, RBP-directed interventions may amplify antitumor immune responses and offer new combinatorial treatment paradigms for cancer and chronic inflammatory diseases.

For instance, the splicing factor SF3B1 is highly expressed in ovarian cancer and is associated with reduced infiltration of cytotoxic immune cells. Inhibition of SF3B1 induces tumor cell pyroptosis and promotes the release of mitochondrial DNA, which is subsequently engulfed by macrophages, driving their polarization toward a pro-inflammatory M1 phenotype and reshaping an immune-activated TME. Treatment with the SF3B1 inhibitor pladienolide B enhances immune cell infiltration and upregulates PD-L1 expression, thereby synergizing with anti–PD-L1 therapy to elicit potent antitumor effects (Wang S. et al., 2023). The RNA-binding protein IGF2BP2 is highly expressed in the GE-9 epithelial subpopulation of breast cancer and promotes macrophage recruitment via CCL2 signaling, leading to polarization toward M2-like and SPP1⁺ macrophages. This process establishes an immunosuppressive TME and attenuates the efficacy of immunotherapy (Li et al., 2024). Targeting IGF2BP2 effectively remodels the TME, enhances therapeutic responsiveness, and improves clinical outcomes. Radiotherapy (IR) has been shown to upregulate YTHDF2 expression, thereby promoting the expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs), which in turn dampen antitumor immunity and increase radioresistance (Wang L. et al., 2023). Deletion of Ythdf2 in myeloid cells reshapes the MDSC compartment, suppresses their infiltration and immunosuppressive functions, and enhances antitumor immune responses. Mechanistically, IR-induced YTHDF2 expression depends on NF-κB signaling, while YTHDF2 reciprocally activates NF-κB by promoting the degradation of mRNAs encoding negative regulators of NF-κB, forming a positive IR–YTHDF2–NF-κB feedback loop (Wang L. et al., 2023). Inhibition of YTHDF2 alleviates MDSC-mediated immunosuppression and improves the efficacy of radiotherapy and combined radio-immunotherapy. Similarly, SRSF10 enhances tumor glycolysis and lactate production, establishing an SRSF10–glycolysis–H3K18 lactylation (H3K18la) positive feedback loop that promotes M2 macrophage polarization and suppresses CD8⁺ T cell activity, thereby constructing an immunosuppressive TME (Luo et al., 2024). Mechanistically, SRSF10 stabilizes MYB mRNA, upregulating key glycolytic enzymes such as GLUT1, HK1, and LDHA, leading to lactate accumulation. Lactate not only enhances SRSF10 expression through H3K18la in tumor cells but also induces H3K18la in macrophages, activating pro-tumor macrophage functions. Pharmacological inhibition of SRSF10 with the small-molecule inhibitor 1C8 enhances the therapeutic efficacy of anti–PD-1 antibodies, identifying SRSF10 as a potential biomarker and intervention target for immunotherapy resistance.

Strong evidenc showed that, the m⁶A “reader” protein YTHDF2 maintains the pro-tumor phenotype of TAMs by regulating IL-10–STAT3 and IFN-γ–STAT1 signaling pathways (Ma et al., 2023). Loss of YTHDF2 reprograms TAMs toward an antitumor phenotype, enhances antigen presentation capacity, boosts CD8⁺ T cell–mediated antitumor immunity, and suppresses tumor growth (Chen et al., 2025c). Accordingly, TAM-targeted inhibition of YTHDF2 enhances the efficacy of PD-L1 blockade, highlighting its potential as an immunotherapeutic target. In B-cell malignancies, YTHDF2 exhibits dual mRNA reader functions. On one hand, it stabilizes key transcripts through m⁵C–PABPC1 interactions, enhancing ATP production and driving B-cell transformation and tumorigenesis (Chen Z. et al., 2025). On the other hand, YTHDF2 promotes immune evasion via m⁶A-dependent mRNA destabilization. Small-molecule inhibitors targeting YTHDF2 not only suppress tumor growth but also improve the efficacy of CAR-T cell therapy, offering promising strategies for the treatment of B-cell malignancies (Chen Z. et al., 2025). METTL3 enhances the stability of PD-L1 mRNA through m⁶A modification in an IGF2BP3-dependent manner, thereby promoting PD-L1 expression in breast cancer cells. Inhibition of METTL3 or IGF2BP3 reduces PD-L1 expression, enhances T cell activation and infiltration, and strengthens antitumor immune responses, positioning these molecules as potential targets for breast cancer immunotherapy (Wan et al., 2022). NAT10, activated by HOXC8, promotes ac⁴C modification and translation of FOXP1 mRNA, thereby enhancing GLUT4/KHK-mediated glycolysis and increasing lactate secretion (Qin et al., 2024; Li et al., 2025e). This process establishes a lactate-rich TME that facilitates the immunosuppressive activity of regulatory T cells (Tregs). Inhibition of NAT10 significantly enhances the antitumor efficacy of PD-L1 immune checkpoint inhibitors, suggesting its therapeutic potential in cervical cancer immunotherapy. Our recent findings further demonstrate that RBMS1 acts as an immunosuppressive RNA-binding protein in triple-negative breast cancer by stabilizing B4GALT1 mRNA, thereby promoting PD-L1 glycosylation and immune evasion (Zhang et al., 2022c). Targeting RBMS1 enhances T cell–mediated antitumor immunity and improves the efficacy of immune checkpoint blockade and CAR-T therapy. Despite their considerable therapeutic promise, the clinical translation of RBP-targeted strategies faces multiple challenges. First, RBPs often exhibit context-dependent expression patterns and functional diversity across different cell types and tissues, raising concerns about off-target effects and systemic toxicity (Zhang et al., 2022c). Second, RBPs frequently participate in multiple signaling pathways, rendering their functions highly complex and necessitating precise spatiotemporal control. In addition, successful clinical application requires overcoming key challenges related to in vivo delivery efficiency, stability, and long-term safety of nucleic acid–based or small-molecule therapeutics. The high functional plasticity of RBPs presents both challenges and opportunities for their development as cancer biomarkers and therapeutic targets. From a biomarker perspective, measurement of total RBP mRNA or protein levels alone is often insufficient to accurately predict patient prognosis. Instead, characterization of specific splice isoforms, post-translational modifications, or subcellular localization may more faithfully reflect functional states. Therapeutically, the dual roles of RBPs increase target selection complexity, as RBPs that promote tumorigenesis in certain cancers may exert protective functions in other tissues or disease stages, and indiscriminate inhibition could result in unintended adverse effects. Moreover, targeting a single pathway may drive RBPs to engage alternative oncogenic networks, leading to therapeutic resistance or tumor recurrence. Therefore, comprehensive dissection of the context-specific determinants governing RBP function-such as specific post-translational modifications or interacting partners-will be essential for developing more selective and personalized therapeutic strategies. Looking ahead, integration of high-throughput drug screening, single-cell omics, and structural biology approaches will enable systematic mapping of RBP-mediated immune regulatory networks, accelerating their translation as immunotherapeutic targets and advancing the realization of precision immunotherapy.

RBPs play fundamental roles in macrophage polarization, survival, programmed cell death, and metabolic reprogramming by orchestrating complex post-transcriptional regulatory networks. These networks not only determine macrophage functional states in inflammation, infection, and tumor microenvironments but also unveil new therapeutic opportunities for immunomodulation. Future studies integrating single-cell technologies, multi-omics analyses, and spatial transcriptomics will be essential for delineating the context-dependent functions of RBPs across diverse tissues and pathological conditions. As an emerging class of immunotherapeutic targets, RBP-directed strategies possess the capacity to modulate multiple signaling pathways and optimize macrophage function, holding great promise for the treatment of cancer and chronic inflammatory diseases and providing a robust theoretical and practical foundation for precision immune interventions.

Recent studies have highlighted the dynamic interplay between tumor cells and the immune microenvironment as a critical determinant of cancer progression and therapeutic response (Gong et al., 2025). In particular, macrophage-driven remodeling of the tumor immune microenvironment has emerged as a key mechanism underlying immunosuppressive states, metabolic adaptation, and resistance to immunotherapy (Gong et al., 2025; Mu and Najafi, 2021). Growing evidence indicates that post-transcriptional regulatory programs, including those orchestrated by RNA-binding proteins (RBPs), are central to shaping macrophage phenotypes and their functional plasticity within the TME, thereby influencing antitumor immunity and treatment outcomes (Gong et al., 2025). From a translational perspective, several practical considerations must be addressed before RBPs can be effectively targeted for therapeutic intervention. Given the pleiotropic and often context-dependent functions of RBPs, achieving sufficient target specificity while minimizing off-target effects and systemic toxicity remains a major challenge. In addition, the feasibility of delivering RBP-targeting agents, particularly in a cell type–or tissue-restricted manner, will be critical for maximizing therapeutic efficacy. Emerging strategies, including RNA-based therapeutics, small-molecule inhibitors, and targeted delivery platforms, may help overcome these limitations. Importantly, rational combination of RBP-targeted approaches with immune checkpoint blockade holds promise for reprogramming the tumor immune microenvironment, enhancing antitumor immunity, and improving patient responses to immunotherapy. Addressing these challenges will be essential for translating mechanistic insights into clinically viable RBP-based therapeutic strategies.