APC is the most frequently mutated gene in colorectal cancer, which drives tumorigenesis by increasingly more complex mechanisms beyond activation of Wnt-β-catenin signaling. In this issue of Cell Research, Ma et al. reports that APC truncation causes immune suppression by promoting PTPN13-mediated deactivation of STAT1, inhibition of which boosts anti-tumor immunity.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide.1 Although the prognosis has slowly improved during the past decades, metastatic CRC remains a significant clinical challenge, with 5-year relative survival rates still hovering around 15%.1 APC, TP53, and KRAS are the most frequently mutated genes in CRC, yet the mechanisms by which these mutations drive tumorigenesis are not fully understood. More than 80% of CRC cells exhibit mutations in the APC gene, which generally lead to APC protein truncations of various lengths.2 The APC protein serves as a scaffold, bringing together components of the β-catenin destruction complex to degrade β-catenin (Fig. 1a). When APC is truncated, this complex cannot properly form, causing β-catenin to build up, leading to overactive Wnt signaling (Fig. 1b),3 which not only dysregulates CRC progression but also suppresses the immune response within the tumor microenvironment (TME).3 Consequently, considerable effort has been directed towards developing therapies that specifically target Wnt-β-catenin signaling in APC-truncated CRC cells3,4; however, a universally accepted, clinically-validated therapy has yet to emerge. In addition, most APC-truncated CRC cases are classified as the microsatellite stable subtype that is resistant to immune checkpoint inhibitor (ICI) therapies.5 Therefore, there is a critical need to elucidate the molecular mechanisms of APC-driven CRC pathogenesis and to develop effective therapies for patients with these specific genetic alterations.

Fig. 1: A proposed mechanism of PTPN13-mediated immune evasion by CRC cells harboring APC truncation.
Fig. 1: A proposed mechanism of PTPN13-mediated immune evasion by CRC cells harboring APC truncation.
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a The signaling activity of β-catenin is kept low by the β-catenin destruction complex that constantly phosphorylates and ubiquitinates β-catenin for proteasome degradation until binding of Wnt ligands to FZD and LRP5/6 receptors disrupts the complex. The C-terminus of APC also binds the PDZ2 domain of PTPN13, preventing it from deactivating STAT1 phosphorylated (pY701) by interferon-γ receptor (INFγR)-activated JAK1. pY701-STAT1 homo-dimerizes and translocates to the nucleus to drive transcription of target genes involved in the MHC Class I antigen presentation. PTPN13 has an N-terminal KIND domain, followed by a FERM, five PDZ domains, and a phosphatase (PTP) domain. STAT1 contains a coiled-coil domain (CCD), a DNA-binding domain (DBD), and an SH2 domain. CK1α, casein kinase 1α; GSK3α/β, glycogen synthase kinase 3α/β. b In APC-truncated (ΔAPC) CRC cells, the β-catenin destruction complex is weakened, leading to stabilization of β-catenin and hyperactivation of β-catenin signaling. Also, PTPN13 freely dephosphorylates pY701-STAT1, resulting in reduced MHC Class I antigen presentation and immune evasion. In addition, truncated APC can directly interact with other proteins, such as Asef and METTL3, to promote metastasis and immune suppression.

APC is a large multi-domain protein that have multiple functions beyond its role in suppressing Wnt-β-catenin signaling.2 They include regulation of cytoskeleton, cell cycle, DNA repair, genomic stability, and other signaling pathways, and disruption of these functions by APC truncation contributes to CRC tumorigenesis. Furthermore, truncated APC proteins can actively promote cancer progression via specific protein–protein interaction. For instance, truncated APC proteins bind directly to and activate a Rho guanine nucleotide exchange factor, Asef, which promotes cancer cell invasion into surrounding tissues via RhoA and Cdc42 pathways6 (Fig. 1b). Truncated APC proteins also directly bind and upregulate METTL3, a key RNA methyltransferase.7 Upregulation of METTL3 in CRC cells activates the JAK1-STAT3 signaling axis, promoting CRC metastasis via upregulation of vascular endothelial growth factor A and cyclin D18 (Fig. 1b).

Truncated APC proteins also drive CRC progression by fostering an immunosuppressive TME. Wu et al. 7 recently reported that upregulated METTL3 in APC-truncated CRC cells upregulated HIF1α which suppressed antitumor immunity by recruiting myeloid-derived suppressor cells via a chemoattractant cytokine MCP-1 and promoting the expression of an immune checkpoint protein VISTA in CRC cells. Through a tour-de-force study, Ma et al. 9 now proposes a novel mechanism of immune suppression via APC, presenting an actionable target for therapeutic intervention. Using genetically engineered mouse models and syngeneic CRC cell models, they found that APC deletion reduced infiltration of CD8+ T cells into TME and conferred resistance to PD1 ICI. Through CRISPR screening, they then identified PTPN13 as a key regulator. PTPN13 is a cytosolic protein phosphatase that can dephosphorylate diverse STAT proteins,10 among which STAT1 promotes the MHC Class I antigen presentation by transcribing IRF1, resulting in enhanced CD8+ T cell infiltration into the TME and robust tumor suppression (Fig. 1a).11 Ma et al. 9 found that the C-terminus of WT APC directly interacts with the PDZ2 domain of PTPN13, preventing PTPN13 from binding to and deactivating STAT1 (Fig. 1a). With APC truncation that eliminates APC–PTPN13 interaction, PTPN13 freely interacts with and dephosphorylates STAT1 to inhibit IFNγ-STAT1-IRF1-MHC Class I pathway, leading to tumor immune evasion (Fig. 1b). Furthermore, a peptide derived from the C-terminal APC specifically bound the PDZ2 domain of PTPN13, blocked PTPN13–STAT1 interaction, and activated STAT1, which promotes antigen presentation and CD8+ T cell infiltration, thereby enhancing the efficacy of ICI.9

This new discovery opens a promising new avenue for developing therapies targeting CRC with APC truncations; however, several issues require resolution prior to translational application. First, PTPN13 is a multi-functional protein that can serve as tumor suppressor and promotor.10 Thus, therapeutic modulation of PTPN13 necessitates precise cell type specificity. Further, since PTPN13 can deactivate other proteins with distinct pathophysiological functions,10 it is crucial to establish the high specificity of any inhibitors for STAT1 over other proteins including other STAT proteins. Second, multiple pathways have been implicated in immunosuppression in APC-truncated CRC. It is therefore important to elucidate the mechanisms by which different pathways are orchestrated to facilitate the development of effective combinational therapy strategies, boost antitumor immunity and combat resistance to immunotherapy. Third, many patients with CRC tumors have multiple gene mutations. Therefore, it is necessary to understand how APC truncation contributes to CRC progression and immunosuppression in primary and metastatic CRC tumors with diverse mutational backgrounds and evaluate the efficacy of any drug candidates against them both in vitro and in vivo.