Review

Adaptor proteins regulating tumor-associated macrophage polarization during cancer progression

Copyright: © 2026 Wadhonkar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Adaptor proteins serve as essential molecular scaffolds within the tumor microenvironment, linking activated receptors to downstream signaling pathways and coordinating the assembly of multiprotein complexes that modulate immune responses. Emerging evidence suggests that adaptor proteins play a critical role in shaping macrophage phenotypic plasticity. Tumor-associated macrophages exhibit functional heterogeneity and can adopt either anti-tumorigenic phenotypes that promote immune activation or pro-tumorigenic phenotypes that support tumor growth, metastasis, and immune evasion. The dynamic transition between these functional states is tightly controlled by intracellular signaling networks in which adaptor proteins function as key regulatory nodes. Based on available mechanistic studies, we systematically summarize adaptor molecules that govern signaling pathways driving macrophage polarization within the cancer condition. Additionally, this review underscores the significance of adaptor proteins as key modulators of macrophage phenotype and highlights their potential as therapeutic targets for reprogramming macrophages to enhance anti-tumor immunity. Collectively, we provide a conceptual framework for understanding adaptor-mediated immune regulation in cancer and support the development of targeted strategies to shape the tumor microenvironment.

INTRODUCTION

Cancer progression is strongly influenced by complex interactions between cancer cells and the surrounding immune microenvironment, where tumor-associated macrophages (TAMs) represent one of the most abundant and functionally adaptable immune cell populations [1]. In general, macrophages are present in distinct populations defined by both phenotypic markers and developmental origin. Monocyte-derived macrophages express high levels of CD11b, MHC class II, and CCR2 and originate from adult hematopoietic stem cells (HSC) via circulating monocytes [2]. On the other hand, tissue-resident macrophages are marked by elevated F4/80 and CX3CR1 expression and arise from embryonic progenitors, maintaining their populations predominantly through self-renewal within tissues [2]. Macrophages exhibit considerable plasticity that cannot be fully explained by the M1/M2 framework [3]. Advances in single-cell technologies, including single-cell RNA sequencing and mass cytometry, have transformed our understanding of macrophage heterogeneity [4]. This concept is reinforced by single-cell RNA-seq analysis from Xue et al., which uncovered 49 transcriptionally distinct macrophage states across 28 different activation stimuli [5]. Instead of a fixed polarization state, TAMs display adoptable functional behaviors and are continuously reshaped by tumor-derived clues, including soluble factors, extracellular vesicles (EVs), and damage-associated molecular patterns secreted by cancer cells [6–8]. In the tumor microenvironment (TME), macrophages undergo reprogramming and adopt a pro- or anti-tumor phenotype [9, 10]. Anti-tumoral type of macrophages can destroy tumor cells and prevent malignancy, whereas pro-tumoral type of macrophages support tumor growth by suppressing the immune response and facilitating angiogenesis and metastasis [11]. Macrophage responses to stimuli within TME are governed by intracellular signaling networks that link receptor activation to coordinated transcriptional regulation [12]. Within this framework, adaptor proteins facilitate a positive feedback loop within macrophages and cancer cells that drives tumor growth [13]. Dysregulation of these adaptor-mediated signaling has emerged as a crucial mechanism linking tumor cells signals to reprogram macrophages during cancer progression [14].

Adaptor proteins represent an emerging class of proteins that play a significant role in these processes [15]. These adaptor molecules are a class of intracellular proteins characterized by two or more protein-binding domains and lack enzymatic activity, but can facilitate the formation of multi-protein complexes by binding with two or more proteins simultaneously [16]. These adaptor proteins act as molecular bridges, facilitating interactions between receptors and downstream signaling pathways to perform various cellular functions, including cell migration, proliferation, and differentiation [17]. Upon receptor activation, adaptor proteins transmit signals to downstream pathways including NF-κB, TBK1–IRF3/7, MAPK (MEK/ERK), PI3K–Akt, mTORC1, and JAK–STAT signaling [18, 19]. These adaptors serve as regulators in macrophage polarization, which in turn influences cancer progression, immune responses, and the TME via activation or inhibition of the inflammatory pathway [20]. Adaptor protein functions are highly interconnected, and their combined activity determines macrophage functional state within TME see in Figure 1. To understand the role of adaptor-mediated signaling in cancer conditions, adaptor proteins are categorized here based on their TAM functional states. The following are key adaptor molecules crucial in shaping the TME by influencing macrophage polarization, either promoting or inhibiting tumor progression and immune response.

ADAPTORS LINKED TO PRO- AND ANTI-TUMOR MACROPHAGE STATES

Certain adaptor proteins involved in the transmission of signals and govern both pro-and anti- tumor macrophage function, influencing immune activation and tumor progression [21]. These adaptors operate conditionally in response to external stimuli and play a key role in shaping macrophages towards pro- and anti-tumor types within TME. MyD88-dependent signaling exhibits functional duality in TAMs and contributes to antitumor response under the acute phase, while supporting immunosuppressive response in the late phase [22, 23]. In TME, tumor-derived damage-associated molecular pattern (DAMP), such as HMGB1, heat shock proteins, extracellular nucleic acid and necrotic cell particles activate TLR/IL-R1-MyD88-MAPK/NF-κB signaling and contribute to tumor-associated signaling [23, 24]. Similarly, Nucleic acids or cyclic dinucleotide from stressed tumor cells activate TLR-TRIF or cGAS-STING signaling in macrophages, which trigger TBK1/IRF3-mediated response and can control tumor progression or inhibition [25, 26]. DAP12–SIRPβ complex recruits SYK and promotes phagocytosis [27–29], while TREM2-DAP12 signaling reshapes TAMs towards a tumor-supportive type [30]. In this section, we summarize major adaptor proteins that drive macrophage function towards tumor-promoting or tumor-restraining outcomes.

Stimulator of interferon genes (STING)

STING serves as a central adaptor protein in innate immune response and activation, which is triggered by cytosolic nucleic acids derived from bacterial, viral, and damaged self-DNA in the cGAS–STING pathway [31]. Pan-cancer analysis demonstrates that STING protein expression is prevalent across multiple tumor types and correlates with aggressive cancer phenotypes [32]. cGAMP-activated STING serves as a signaling scaffold to recruit and activate TANK binding kinase 1 (TBK1), resulting in TBK1-mediated phosphorylation of STING at Ser366 [33]. This event promotes IRF3 activation and nuclear translocation, ultimately inducing interferon-stimulated genes and type I interferons [34]. Recent studies suggest that this signaling plays a context-dependent role in cancer, simultaneously promoting and restricting anti-tumor immune response across different stages of tumor immune interactions [34]. Lam KC et al. reported that microbiota-derived agonists activate type I interferon-derived signaling in intratumoral monocytes, facilitating macrophage polarization and reprogram TME towards antitumor response [35]. Similarly, Miao et al. showed that STING influences gastric cancer outcome with both its activation by 2′3′-cGAMP or knockdown and polarizes TAMs toward a pro-inflammatory state as well as induces apoptosis of cancer cells via IL6R–JAK–IL24 signaling axis [36]. This adaptor emerged as an interactive therapeutic target in cancer [37–39]. Preclinical studies show that STING agonists improve immune cells infiltration and antitumor immunity [40–42]. However, despite these promising results, most clinical trials of STING agonists have been discontinued or shown limited efficacy, and ongoing studies have yet to deliver the expected therapeutic benefits [43, 44]. These disappointing outcomes highlight the need to better understand context-dependent and alternative roles of STING signaling in cancer therapy.

Myeloid differentiation factor 88 (MyD88)

The MyD88 acts as an adaptor protein and plays a pivotal role in the activation of innate immunity through the activation of immune cells via TLRs signaling. TLRs and MyD88 interaction are mainly associated with the activation of NF-κB and other signaling involved in inflammation [45]. MyD88 mainly elicits the immune response through the activation of NF-kB, AP-1, and IRFs transcription factors [46]. The influence of MyD88 on TME is crucial in cancer progression. MyD88- dependent pathways drive the expression of multiple genes involved in intestinal tumorigenesis and are required for both spontaneous and carcinogen-induced cancer development [22, 47]. Analysis of the glioma patient sample revealed significantly higher expression of MyD88 [46]. Breast cancer cells-derived exosomes initiate the proinflammatory molecules such as TNF-α, IL-6, CCL2, and GCSF in macrophages through the activation of TLR/MyD88/NF-kB signaling [48]. The alliance between TLR and MyD88 leads to recruitment and phosphorylation of IRAK family members, resulting in the activation of the TRAF6 adaptor which further activates TAK1 and subsequently activates IKK complex. Activated IKK phosphorylate IκB, upon phosphorylation, IκB undergoes degradation, which causes release as well as translocation of NF-κB into the nucleus and transcribes inflammatory genes as well as gene require for cell survival. Chen et al. reported in a high-fat diet-induced hepatocellular carcinoma (HCC) mouse model, MyD88 switches macrophages towards tumor supportive type via SREBP1/STAT6 signaling and enhanced non-alcoholic fatty liver disease-related HCC [49]. Interestingly, another study suggests that EMILIN-2, an extracellular matrix (ECM) molecule, triggers the activation of MyD88 dependent TLR-4/NF-κB signaling, promoting M1 macrophage population and affecting CRC development in a murine model [50]. Similarly, in the melanoma mouse model, MyD88/IL-1R signaling has been identified as a key regulator of PD-1 expression on tumor-associated macrophages, supporting their immunosuppressive phenotype [23]. The involvement of MyD88 in macrophage polarization during cancer progression has been reported in various studies. It represents a promising therapeutic target for enhancing macrophage-mediated anti-tumor immune responses.

DNAX-activating protein of 12 kDa (DAP12)

DAP12, a 12 kDa immunoreceptor tyrosine-based activation motif (ITAM) containing transmembrane adaptor protein, expressed in cancer cells as well as in immune cells, including macrophages [30, 51]. DAP12 plays a functional role downstream of the TREM receptor family and plays a critical role in the regulation of immune response. Phosphorylated DAP12 triggers the activation of MAP/ERK signaling, and also controls the expression of inflammatory gene via regulation of NF-kB activation [52]. Interestingly DAP12 involvement is reported in SIRP-ß2 mediated signaling in myeloid cells. It recruited through binding of lysine residues present in transmembrane domain of SIRP-ß2 and promotes cancer cells phagocytosis, T cells activation and support innate anticancer immunity [53]. In the THP-1 monocyte, overexpression of SIRP-ß2 responsible for differentiation of monocytes towards macrophages [53]. Shabo et al. investigation reported that breast cancer patient tissue samples expressed DAP12 plays crucial role in macrophage fusion function and contributes to liver, bone metastasis and poor survival [30]. The study by Aoki et al. demonstrates that under leukemic conditions, the ITAM motif of DAP12 is essential for both macrophage differentiation and the maintenance of cell viability [29]. To target the DAP12 holds potential for improving immunotherapy outcomes in cancer-free survival.

Toll-interleukin-1-receptor (TIR)-domain-containing adaptor-inducing interferon-β (TRIF)

TRIF is an adaptor protein recruited upon activation of TLR3 and TLR4 [54]. The activation of TRIF varies depending on cancer types, which can significantly impact immune response, either enhancing or inhibiting cancer [55, 56]. The expression has been detected in gastric cancer in mice and patient samples [57] and hepatocellular carcinoma patients [58]. TRIF is responsible for activating transcription factors such as interferon regulatory factor 3, nuclear factor kappa B, and activator protein, which contribute to the activation of interferon-β and production of various inflammatory cytokines [26, 59]. The interaction between TLR3 receptor and TRIF relies on the phosphorylation of tyrosine residues Tyr759 and Tyr858 within the cytoplasmic domain of the receptor [60, 61]. The determination of the downstream signaling axis is governed by the cytoplasmic domain of the receptor and its engagement with TRIF. In the production of interferon, TRIF binds with TRAF3 and facilitates the phosphorylation and activation of IRF3. Alongside, TRIF also interacts with TRAF6 and receptor-interacting protein 1 (RIP1) to activate NF-κB and drive inflammatory cytokine production [61]. Recently, Firmal P et al. reported that LPS stimulates the expression of SMAR1 via the TLR4-TRIF signaling axis, regulating STAT3 expression, and exerts antitumor effects by altering TAM towards the M1 phenotype of macrophages in the cell line of CRC [62]. The role of TRIF has also been investigated in apoptosis when overexpressed in 293T cells [63]. TRIF can be used as a potential target for immune modulation, contributing to the development of novel cancer immunotherapeutic strategies.

ADAPTOR LINKED TO IMMUNO-REGULATORY PRO-TUMOR MACRO-PHAGE STATE

The adaptor proteins mediated pro-tumoral macrophage reprogramming influenced by TME composition, including cancer cells-derived proteins as well as extracellular vesicles secreted in the surrounding [64, 65]. Within the TME, adaptor molecules participate in NF-κB, MAPK, PI3K-AKT, and IRF signaling pathways and alter macrophage fate towards tumor-supportive phenotypes. For example, growth factors and cytokines bind to their respective receptors, trigger phosphorylation, and recruit GRB2, which activates RAS-MAPK and PI3K-AKT signaling and governs macrophage polarization [66, 67]. TIRAP plays a functional role downstream of the TLR receptor and initiates NF-κB-dependent tumor-supportive state in macrophages [68]. In response to growth factor or G-protein-coupled receptor, the RIAM adaptor molecule is involved in PI3Kγ signaling and promotes immunoregulatory macrophage polarization [68, 69]. LAMTOR1, v-ATPase, mTORC1, and LXR-dependent gene expression support M2-like tumor supportive macrophage transition within TME [70]. Similarly, TRAF family adaptors are involved in TNF/IL1R/TLR signaling and promote tumor progression [71]. Cancer cells secreted VEGF, which activates SYK-CARD9-BCL-10-MALT1 signaling, promotes NF-κB mediated tumor supportive macrophage phenotype within TME [14]. Interesting finding suggested co-culture of THP-1 macrophages with oral squamous cell carcinoma-derived supernatant containing IL-1 and IL-6 activates respective receptors, recruits RACK1, and drives NF-κB signaling that promotes M2-like TAMs phenotype [72]. The STAP family receptor also acts downstream of the IL-6 receptor and STAP1/2-STAT3 signaling, promoting anti-inflammatory microglia in glioma [73]. Condition media from prostate cancer cells increases TRIB1 expression, resulting in suppression of IKB-zeta signaling, and leading to increased Bcl-3 and STAT3 activity, which promotes M2-like macrophage differentiation [74, 75]. Here, we provide a comprehensive overview of adaptor proteins that influence signaling pathways governing macrophage phenotypic switching toward tumor-supportive functions within the TME (see Figure 1).

Grb2-associated binder2 (Gab2)

Gab2 belongs to the Gab family of proteins, which are characterized by their association with tyrosine kinases and the recruitment of phosphotyrosine-rich domain-containing molecules. These proteins play a crucial role in signaling mechanisms, significantly influencing cellular differentiation, proliferation, migration, and apoptosis [76]. The expression of Gab2 in different cancers has already been reported, such as in colorectal cancer patients’ tissue samples (CRC) [77], in the bone marrow and peripheral blood samples from chronic myeloid leukemia [78], breast cancer cells and cell line [79], and ovarian cancer patients [80], highlighting its role in tumor angiogenesis, metastasis, and progression. In the literature, it has been found that macrophages express Gab2, and the Gab2/SHP2/PI3K signaling pathway plays a key role in regulating cytokine secretion and phagocytosis in these cells [81]. Macrophages influence cancer progression through polarization shifts that change the balance of the TME [82]. Recently, the study done by Gao X et al. reported that CRC cells derived condition media treated TAM shows overexpression of Gab2, which is associated with poor prognosis [83]. In CRC patients, Gab2 polarizes the macrophages towards a tumor supportive state through the AKT and ERK signaling and promotes CRC growth as well as metastasis [83] The mechanism and influence of Gab2 on phenotype changes of TAMs remain unclear; the detailed mechanism of Gab2 control macrophage polarization provides further insight to develop new immunotherapeutic strategies targeting TAMs during cancer progression.

Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP)

The MyD88 adaptor-like (MAL)/TIRAP binds with MyD88 through the cytoplasmic TIR- domain and acts as bridge between Toll-like receptor 2/4 and its downstream signaling molecule to orchestrate the inflammatory response [84]. TIRAP can form homodimers or hetero dimers with MyD88 and activate AP-1 or NF-κB transcription factor-mediated proinflammatory response [85]. The expression of TIRAP has been reported in CRC cell lines [86], non-small cell lung cancer (NSCLC) [87], breast cancer cells [88], as well as in many other cancer types. In the coculture of LX2 and THP-1 condition, demethylation of TIRAP mRNA mediated by ALKBH5 controls the CCL5-CCR5 signaling pathway, which in turn promotes the recruitment of monocytes and M2 polarization of macrophages in liver fibrosis and hepatocellular carcinoma [89]. In macrophages, the TIRAP-mediated proinflammatory signaling axis binds with IRAK2, C-jun, as well as kinases like PKCδ and p38 MAPK [90]. The negative regulators SOCS1, CLIP170, IRAK1/4, and Triad3A are associated with ubiquitination and proteasomal degradation of TIRAP [84]. Despite TLR signaling remains persistently active in cancer, and the involvement of TIRAP in macrophage polarization is well established, its precise contribution to macrophage polarization within cancer remains unclear, underscoring a critical area for further investigation. Bridging this knowledge gap through targeted mechanistic investigations may help identify TIRAP-driven pathways as promising therapeutic opportunities for reprogramming tumor-associated macrophages.

Rap1-interacting adaptor molecule (RIAM)

Rap1-interacting adaptor molecule is a crucial component in cellular responses and plays a crucial role during cell adhesion, migration, proliferation, and immune cells modulation in melanoma and prostate cancer [91]. RIAM belongs to the MRL (Mig-10/RIAM/Lamellipodin) family of adaptor proteins and functions as a mediator protein for Rap1 [92]. RIAM not only engages with activated Rap1 but also another signaling molecule through the Ras-association (RA) domain, a pleckstrin homology (PH) domain, and several proline-rich sequences [93]. Patsoukis N et al. reported RIAM integrates critical signaling pathways essential for the regulation of integrin-mediated immune responses and cancer progression [94]. In macrophage polarization, RIAM can direct reprogramming of macrophages towards tumor supportive phenotype and facilitate tumor progression, which has already been reported in the melanoma mice model [95]. RIAM plays a key role in the phagocytosis process by acting downstream of Rap1 and facilitating the engulfment of particles by macrophages. It achieves this by recruiting talin to complement receptors and rendering RIAM essential for complement-mediated phagocytosis in macrophages [95]. Overall, RIAM serves as a critical node for signal transduction in various immune cell processes and cancer progression.

Late endosomal/lysosomal adaptor, MAPK and MTOR activator 1 (Lamtor1)

LAMTOR1 is an adaptor, connecting heterodimers, and is essential for the formation of regulator pentamer, which is required for mTORC1 activation during cellular signaling and organelle function [96]. LAMTOR1 can also act as a crucial anchor for p14-MP1–MEK–ERK axis within late endosomes and lysosomes, as well as activate RhoA and RhoC, and may shape actin remodelling [97]. Downregulation of LAMTOR1 has an impact on lysosomal activation and induces ROS-p53-dependent apoptosis [97]. The LAMTOR1 is essential in the proliferation of CD4+ T cells and the suppressive function of T regulatory cells [98]. The expression of LAMTOR1 has been reported in the cell lines of bladder cancer [99], non-small-cell lung cancer patient tissue [100], colon cancer mouse model [101] etc. LAMTOR1 undergoes LYS 63-linked polyubiquitination, which is influenced by TRAF4 ligase, which enhances regulators’ GEF activity, activates mTORC1, and influences inflammation-driven CRC [101]. The mTOR signaling influences the functional as well as metabolic differentiation of the pro- and anti-inflammatory polarization of macrophages within TME [102]. LAMTOR1 is crucial for immune-suppressive-type signaling by linking immune responses with metabolic processes [70]. Another study demonstrated that Lamtor1–/– macrophages, S6K phosphorylation is impaired, and 25-hydroxycholesterol levels are reduced, leading to altered LAMTOR1, v-ATPase, mTORC1, and LXR-dependent gene expression essential for M2 macrophage differentiation while simultaneously enhancing pro-inflammatory cytokine production in mice [96]. Researchers have already proposed Lamtor1 as a therapeutic target in cancer, primarily due to its role in promoting a tumor-supportive type of macrophage phenotype.

Tumor necrosis factor receptor-associated factor (TRAF)

The TRAF family of proteins consists of cytoplasmic adaptor proteins that bind directly with the intracellular domains of cell surface receptors and was initially identified through their association with members of the TNF receptor superfamily [103]. In mammals, the TRAF family currently comprises six classical members (TRAF1-TRAF6) that possess a conserved TRAF domain at the carboxy terminus, and one nonclassical member (TRAF7) that lacks this TRAF domain [71]. The involvement of the TRAF family adaptor has been found in cell proliferation, differentiation, survival, and apoptosis, as well as in immune modulation [71]. In mouse models, TRAF1 and TRAF4 influence skin and lung carcinoma [104–106]. TRAF2 promotes tumor development in breast [107] and gastric cancer in mice and patient samples, respectively [108]. TRAF5 contributes to the development of CRC within human patients [109]. TRAF6 is upregulated in several tumor types, including colorectal, gastric, breast cancer, and is specifically involved in binding with TNF receptor as well as IL1R/TLR signaling [71]. Tan et al. reported, baicalin mediates the autophagic degradation of TRAF2 in TAMs, thereby modulating TRAF2/TRAF3 interactions with IKKα/RelB/p52 signaling axis [110]. This indirect activation of the RelB/p52 signaling pathway upregulates CXCL12 and CCL9 expression, leading to overexpression of IL-6 and TNF-α, and promotes the polarization of TAM from anti-tumor to tumor-supportive types in the orthotopic HCC implantation mice model [110]. In CRC, an increase in M1 macrophage populations was detected after TRAF6 knockdown in a mouse model [111]. In TME, TRAF2 modulates the production of inflammatory cytokines in TAMs and promotes tumor progression [112]. Elucidating more mechanistic insights into TRAF family adaptor-mediated signaling will open new opportunities for developing effective therapeutic interventions in cancer.

Caspase-recruitment domain-containing adaptor protein (CARD9)

CARD9 adaptor is a crucial regulator involved in innate and adaptive immunity and modulates inflammatory responses and oxidative stress by controlling the expression as well as production of key cytokines and chemokines [113]. CARD9 facilitates tumor cell proliferation and migration, and contributes to cancer development [114] and is expressed in lung adenocarcinoma patients [115], ovarian cancer tissue and cell lines [116], CRC [117]. In the colitis‐associated cancer mice model, CARD9 signaling axis drives IL-1β production in the damaged intestine, which stimulates IL-22 secretion in lymphoid cells, leading to STAT3 activation and subsequent tumorigenesis in transformed epithelium [118]. The overexpression of CARD9 is reported in the infiltrated macrophages, which results in increased secretion of tumor growth-supporting cytokines (IL-10 and IL-1α) while reduced levels of the tumor growth-inhibiting cytokine IL-12, and contributes to tumor metastasis during colon cancer progression [14]. In human CRC progression, upregulated expression of CARD9 in infiltrating macrophages has been observed [14]. Mechanistically, CARD9 changes the phenotype of macrophages towards metastasis-promoting type through the activation of the NF-κB signaling pathway [14]. The involvement of CARD9 in tumor cell proliferation and metastasis emphasizes its potential as a therapeutic target in anti-cancer strategies.

Signal-transducing adaptor protein (STAP)

The signal-transducing adaptor protein (STAP) family comprises two adaptor molecules STAP-1 and STAP-2, which contain a Pleckstrin homology (PH) domain in their N-terminal region and contribute to multiple signaling cascades [119]. The expression of STAP-1 is upregulated in chronic myeloid leukemia (CML) stem cells [120], while STAP-2 is expressed in a variety of immune cell types and tissues [121]. Studies reported that in the orthotopic mice model, expression of STAP1 in glioma-associated microglia positively correlates with tumor aggressiveness as well as poor prognosis in glioma and potentially facilitates M2-like polarization through IL-6/STAT3 signaling and inhibiting phagocytosis [73]. STAP-2 mediates Brk-dependent phosphorylation and activation of STAT3 and STAT5 to promote breast cancer cells proliferation [122]. STAP-2 is highly expressed in prostate cancer and upregulates the epidermal growth factor receptor (EGFR) signaling [123]. STAP-2 also serves as a critical regulator of both innate and adaptive immune responses by engaging in cytokine signaling axis through its interactions with STAT family transcription factors [124]. In Raw macrophages, STAP-2 directly promotes LPS-induced activation of the NF-κB signaling pathway through its interaction with MyD88 and IKK-αβ and serves as a novel adaptor protein that links MyD88 and IKK-αβ in TLR4 signaling [125]. The involvement of these adaptors in macrophage polarization during malignancy could offer valuable insights into their potential therapeutic applications in cancer treatment.

Receptor for activated C kinase 1 (RACK1)

Receptor for activated C kinase 1 (RACK1) belonging to the tryptophan-aspartate repeat (WDR) scaffold protein family and identified as an interacting partner of activated PKC kinase [126]. RACK1 has been engages with receptor proteins as well as protein kinases and play a role in various biological processes, including cell migration [127], angiogenesis [128], and cancer metastasis [129]. RACK1 is widely expressed in normal tissues and is significantly upregulated in different kinds of cancer and is believed to contribute to the development and progression of cancer [130]. The upregulated RACK1 expression positively correlates with tumor differentiation and lymph node metastasis in colon cancer, while negatively associated with patient survival [130]. RACK1 also promotes tumorigenicity in non-small cell lung cancer [131], oral squamous cell carcinoma (OSCC) [132], pulmonary adenocarcinomas [133], and breast cancer [134]. The study conducted by Dan et al. demonstrated that in a clinical sample of patients, RACK1 can inhibit the activation of nuclear factor-kappa B (NF-κB), modulate the expression of IL-6, CCL5, and CSF released by tumor cells, and attenuate prolonged inflammatory responses in oral squamous cell carcinoma (OSCC) [72]. The upregulated RACK1 expression in OSCC inhibits macrophage activation but promotes an increased proportion of M2/M1 ratio in vitro as well as in vivo and fosters malignancy [72]. By regulating crucial signaling mechanisms, RACK1 contributes to cancer progression and could be considered a potential therapeutic target for cancer treatment.

Tribbles 1(TRIB 1)

TRIB1 (Tribbles homolog 1) belongs to the evolutionarily conserved mammalian tribbles homolog pseudokinase family and serves as an adaptor instead of direct phosphorylation of the target molecule [135]. The lack of a functional adenosine 5’-triphosphate (ATP) binding site serves as a scaffold and facilitates the assembly of other proteins [136]. The expression of TRIB1 exhibits a positive correlation with the levels of nuclear factor NF-κB and interleukin-8 in breast cancer patients [74, 137]. IL-8 is involved in the activation of the surface receptors CXCR1 and CXCR2 expressed by TAM and induces to secrete more growth factors [138]. In the murine breast cancer model, TRIB1 controls cancer proliferation by modulating the phenotypes of TAMs [139]. In the mouse model, TRIB1 influences cytokine secretion by inhibiting IκB-zeta in prostate cancer cells, which promotes the differentiation of monocytes into M2 macrophages and facilitates prostate cancer progression [74]. TRIB1 interactions with various cellular signaling molecules suggest its potential as a biomarker for cancer prognosis and as a target for novel therapeutic strategies.

p62 (SQSTM1)

p62 is a conserved, multifunctional adaptor molecule involved in many important cellular processes, and upregulated expression was found in many cancer cells, which supports cancer progression [140, 141]. Because of its distinct domain architecture, p62 binds with multiple binding partners and modulates pathways controlling tissue homeostasis, inflammation, and cancer [142]. p62 positively increases NF-κB activity at the molecular level and contributes to inflammation and cancer progression [142]. P62 also contributes to host metabolic control by altering the activity of immune cells within the TME [143]. It enhances lactate production in cancer cells by regulating glucose metabolism, promoting TME acidification, leading to changing macrophage phenotype towards an M2-like state, and contributing to tumor evasion [143]. In the glioma mouse model, immunity-related GTPase M (IRGM) switches macrophages towards M2-like macrophage phenotype via the p62/TRAF6/NF-κB pathway and promotes glioma progression [144]. In another interesting study, it was found that silencing of p62 diminishes ox-LDL-induced proinflammatory response in macrophages by inhibition of mTOR/NF-κB signaling pathways [145]. More mechanistic insights into p62-mediated inflammation and cancer progression may guide the discovery of new therapeutic interventions. The development of small-molecule agents against p62 has been identified as a promising therapeutic avenue in hepatocellular carcinoma management [143].

IMPACT OF ADAPTOR MOLECULE ON CANCER PROGRESSION AND METASTASIS

Following the discussion of individual adaptor proteins in TAM polarization, we now examine their roles in cancer progression, metastasis, and immune evasion. For example, the GRB2 adaptor is expressed in different cancers and serves an important role in tumor angiogenesis, metastasis as well as progression through the activation of AKT and ERK signaling [83]. Breast cancer cells expressing DAP12 show an impact on macrophage functions and contribute to liver, bone metastasis and poor survival [30]. The adaptor, like MYD88, TIRAP, and TRIF activated through TLR signaling and significantly contributes to TME and macrophage polarization [48, 62, 89]. RIAM can influence the reprogramming of macrophages into a tumor-promoting M2 phenotype, which aids in tumor progression [95]. LAMTOR1 mediates the polarization of macrophages toward the M2 phenotype [70]. TRAF family proteins also govern macrophage polarization according to their interactions, leading to either pro-inflammatory or anti-inflammatory responses within the TME [110, 146]. In CRC, CARD9 promotes tumor growth by enhancing the expression of anti-inflammatory cytokines such as IL-10 and IL-1α, while simultaneously reducing the expression of IL-12 in tumor-infiltrating macrophages [14]. The STAP1 expression in glioma-associated microglia correlates with tumor aggressiveness and inhibits phagocytosis by promoting M2-like polarization through IL-6/STAT3 signaling [73]. In OSCC overexpression of RACK-1 increases the proportion of M2/M1 ratio of macrophages and contributes to malignancy [72]. The involvement of adaptor proteins in tumor proliferation and metastasis highlights their potential as therapeutic targets in anti-cancer strategies.

THERAPEUTIC STRATEGIES TAR-GETING ADAPTOR MOLECULES

Therapeutic strategies targeting adaptor molecules offer a promising approach in the fight against a range of diseases, including cancer [147]. Adaptor molecules play critical roles in cellular signaling pathways that govern tumor growth, metastasis, and immune responses [21]. Targeting adaptor protein interactions using small molecules or peptides represents a potential strategy to alter TAM response in cancer [148, 149]. Gene-silencing approaches such as siRNA or CRISPR/Cas9 can downregulate adaptor expression, while interfering with receptor–adaptor binding or modulating post-translational modifications may further impair pro-tumoral macrophage activity. Lin Xie et al. reported that the synthetic compound TJ-M2010-5 targets MyD88 homodimerization and effectively prevents colitis-associated CRC [150]. Another investigation reported that ST2825, a MyD88 inhibitor, effectively suppresses the activation of the NF-κB/AKT1/p21 signaling axis and increases cell cycle arrest and apoptosis in pancreatic cancer cells [151]. Ewa Witort et al. employed a combination of antisense oligonucleotides and a proteasome inhibitor targeting the tumor necrosis factor receptor type 1-associated death domain (TRADD) adaptor to treat chemoresistant hepatocellular carcinoma cells [152]. Adaptor proteins have gained significant attention recently because of their crucial role in cancer. Several clinical trials have shown promising results by targeting TAMs in various cancer types [153, 154]; however, these approaches have not specifically focused on adaptor proteins. Although preclinical studies highlight the role of adaptor proteins in macrophage polarization and cancer progression, no clinical trials or approved therapies currently target these molecules in macrophages. This remains an important and emerging area for future investigation. Despite increasing evidence linking adaptor proteins to macrophage polarization and tumor progression, their therapeutic targeting remains challenging. Adaptor proteins function within complex and interconnected signaling networks, where redundancy and compensatory pathways allow cancer and immune cells to bypass the inhibition of individual adaptors [155, 156]. In addition, many adaptor proteins participate in multiple physiological pathways, raising concerns about specificity and potential systemic effects. Therefore, a deeper understanding of their context-dependent functions and interactions within the TME is required before adaptor-targeted strategies can be effectively translated into cancer immunotherapy.

CONCLUSIONS

Adaptor proteins are essential for regulating TAM polarization during cancer progression. These molecules serve as molecular bridges, promoting interactions between cell-surface receptors and downstream signaling molecules within the TME, and they influence cancer growth and metastasis. Recent studies have emphasized the critical role of adaptor proteins in macrophage reprogramming see Table 1. Collectively, these adaptor proteins can serve as potential therapeutic and diagnostic targets in cancer. Investigating the role of adaptor proteins in this context could lead to the development of novel therapeutic strategies targeting macrophage plasticity in cancer treatment and to innovative strategies for reprogramming TAMs toward anti-tumor phenotypes, ultimately improving outcomes in cancer treatment. Although recent advances have elucidated the roles of several adaptor proteins in TAM polarization, the majority of studies remain at the preclinical stage. Moreover, the context-dependent dual functions of certain adaptors (e.g., STING, MyD88, DAP12) in promoting both anti- and pro-tumor phenotypes underscore the complexity of adaptor-mediated signaling within the TME. Future investigations should focus on clarifying cell-type-specific adaptor functions using single-cell transcriptomics [157], developing highly selective small-molecule inhibitors or PROTACs that target critical adaptor–receptor interactions [158], and exploring combination strategies involving immune checkpoint blockade or TAM-depleting agents [159, 160]. Considering the crucial role of adaptor proteins in signal transduction [161], we can expect significant advancements in this area of research in the future. Such progress will enhance our appreciation and understanding of adaptor proteins in signal transduction and their potential as therapeutic targets.

AUTHOR CONTRIBUTIONS

Conceptualization and supervision: MSB; Writing (Original Draft): MSB, KW, TO; Editing MSB, KW, TO. All authors have read and agreed to the published version of the manuscript.

ACKNOWLEDGMENTS

The authors acknowledge the Indian Institute of Technology Indore (IITI) for providing the necessary facilities and support. We also thank Dr. Santhoshkumar J for his insightful suggestions during the compilation of some of the data in the manuscript.

CONFLICTS OF INTEREST

Authors have no conflicts of interest to declare.

FUNDING

This work was supported by the Department of Biotechnology (DBT), Government of India, sponsored “National Network Project” to MSB (NNP-BT/PR40197/BTIS/137/68/2023). Cumulative Professional Development Allowance (CPDA) and Research Development Fund (RDF) from Indian Institute of Technology Indore (IITI) to MSB.

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