Traditionally, bioinformatics analyses often utilize the differential gene abundance between tumor and normal tissues to screen for target genes (Golub et al., 1999). Typically, genes with significantly higher abundance in tumors than normal tissues are classified as oncogenes and become focal points of research (Bishop, 1991; Croce, 2008). However, a new understanding has emerged with the proliferation of comprehensive databases such as TCGA. Researchers increasingly recognize that not all genes are highly expressed in tumors act as promoters of cancer (Cao et al., 2021; Yan et al., 2019; Boor et al., 2020; Martinez-Turtos et al., 2022). In fact, some genes show high abundance in tumor tissues but are associated with good patients prognosis (Cao et al., 2021; Yan et al., 2019; Boor et al., 2020; Martinez-Turtos et al., 2022). This finding challenges the traditional understanding of tumor biology. Although public databases provide evidence that genes which are highly expressed in tumor tissues and serve tumor suppressor roles are prevalent, they have not been broadly recognized or systematically analyzed by the scientific community. Our work pioneers the classification and definition of these genes as “paradoxical genes,” and it delves deeply into the reasons and context for the existence of these paradoxical genes.

The discrepancy between mRNA and protein levels may be a reason for the emergence of paradoxical genes (Vogel and Marcotte, 2012). This difference is mainly due to post-transcriptional and -translational modifications, which are crucial in the dynamic regulation of gene expression (Vogel and Marcotte, 2012). Post-transcriptional modifications include processes such as alternative splicing, enabling a single gene to generate multiple mRNA variants, thereby expanding the diversity of the proteome (Vogel and Marcotte, 2012; Wahl et al., 2009). The upstream open reading frames (uORFs) can significantly regulate the translation of the main open reading frame (ORF) (Barbosa et al., 2013; Johnstone et al., 2016). Concurrently, post-translational modifications such as phosphorylation and ubiquitination further diversify protein functions and regulation (Hershko and Ciechanover, 1998; Hunter, 2007). However, within the context of TCGA, the focus is solely on the measurement of mRNA abundance (Cancer Genome Atlas Research Network, 2008; Author anonymous, 2012; Weinstein et al., 2013). This is typically quantified using RNA sequencing data, which provides detailed information on the levels of mRNA present in a given sample (Cancer Genome Atlas Research Network, 2008; Author anonymous, 2012; Weinstein et al., 2013). Inconsistencies between gene and protein levels can potentially distort patient prognosis results, contributing to the emergence of paradoxical genes (Akbani et al., 2014).

The tumor immune microenvironment (TIME) is critical for suppressing tumor progression, through its complex network of immune cells, stromal cells, signaling molecules, and extracellular matrix components (Joyce and Fearon, 2015; Fridman et al., 2012; Quail and Joyce, 2013). This dynamic environment can promote or inhibit tumor growth, depending on the balance of pro- and anti-tumor factors (Schreiber et al., 2011). Key players include cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, dendritic cells, B cells, proinflammatory cytokines, and chemokines (Schreiber et al., 2011; Smyth et al., 2002; Palucka and Banchereau, 2012; Nelson, 2010; Müller et al., 2009; Topalian et al., 2015). There is currently evidence that some Paradoxical genes are involved in regulating TIME and inhibiting tumor progression (Cao et al., 2021; Yan et al., 2019; Boor et al., 2020; Martinez-Turtos et al., 2022). The regulatory influence of paradoxical genes on TIME elucidates the mechanism underlying their tumor suppressor effects.

The expression of genes and pathways exhibits context-dependent effects, also known as context specificity, which refer to the phenomenon where the function or behavior of a gene varies depending on the specific context in which it operates (Feil and Fraga, 2012; Huang, 2009; Beyer et al., 2007). In the context of cancer, the role of a gene can vary significantly depending on factors such as the type of cancer, the tissue in which the tumor originates, and the stage of the cancer (Vogelstein and Kinzler, 2004; Hanahan and Weinberg, 2011; Stratton et al., 2009). For instance, genes associated with signaling pathways like TGFβ, NOTCH, and NF-κB demonstrate differential expression across various tumor tissues. The TGFβ pathway presents a dual role, acting as a tumor suppressor in early stages and a promoter in advanced stages, with the expression varying significantly in breast, pancreatic, and colorectal cancers (Massagué, 2008). Similarly, the NOTCH signaling pathway, critical for cell fate determination and differentiation, shows oncogenic as well as tumor-suppressive functions, depending on the cancer type, as observed in breast cancer (BRCA), T-cell acute lymphoblastic leukemia, and lung cancer (Stylianou et al., 2006; Weng et al., 2004; Kopan and Ilagan, 2009). Often, the NF-κB pathway, a key regulator of inflammation and immune responses, is dysregulated in BRCA, multiple myeloma, and colorectal cancer, where it facilitates cell proliferation, survival, and chronic inflammation (Karin, 2006; Annunziata et al., 2007; Greten et al., 2004). The specific roles and expression patterns of these similar pathways in different tumor environments are also one of the reasons for the widespread existence of paradoxical genes.

In this article, by exploring the mechanism of paradoxical genes formation, we seek to broaden the current understanding of tumor biology and provide new ideas for tumor treatment and research.

When genes highly expressed in cancer compared to normal tissues, are identified through bioinformatics analyses, it often implies that these genes may act as drivers of oncogenesis, serve as diagnostic or prognostic biomarkers, or act as predictive markers for treatment response (Niu et al., 2022; Liu Y. et al., 2021). Indeed, the relationship between gene expression and cancer prognosis can be complex and sometimes counterintuitive (Hanahan and Weinberg, 2011). Contrary to what might be expected, high expression of certain genes in tumors can be associated with a more favorable prognosis (Hanahan and Weinberg, 2011). This paradoxical finding highlights the complexity of cancer biology, revealing that genes may play multifaceted roles in tumorigenesis and cancer progression (Hanahan and Weinberg, 2011). For instance, some genes highly expressed in tumors could participate in immune response activation, DNA repair mechanisms, or cellular differentiation processes, potentially inhibiting tumor growth or spread, thereby improving patient outcomes (Blagih et al., 2020; Williams and Schumacher, 2016; Kalluri and Weinberg, 2009). Researchers face a challenge of dissecting the dual roles that some genes, acting as oncogenes in certain contexts while serving protective or suppressive functions in others (Hanahan and Weinberg, 2011).

The central dogma of molecular biology, formulated by Francis Crick, describes the flow of genetic information from DNA to RNA to protein through the processes of transcription and translation (Crick, 1970). While it is generally hypothesized that higher mRNA levels correlate with higher protein levels, this relationship is influenced by several factors (Vogel and Marcotte, 2012; Schwanhäusser et al., 2011; Tian et al., 2004). Post-transcriptional regulation can modify mRNA stability and translation efficiency, as well as the sequence features of the mRNA itself, such as upstream ORFs, can affect how efficiently it is translated (Barbosa et al., 2013; Sonenberg and Hinnebusch, 2009). Protein stability and degradation processes further modulate the levels of functional protein in the cell (Ciechanover and Kwon, 2015; Sherman and Goldberg, 2001). Although studies have typically shown a positive correlation between mRNA and protein levels, the variability suggests that multiple mechanisms, including translation efficiency and protein stability, are significant in determining final protein levels in biological systems (Schwanhäusser et al., 2011; Liu et al., 2016). Several studies have reported average correlation coefficients around 40%–60%, indicating that mRNA levels indicate protein abundance but are far from perfectly predictive due to various biological and methodological confounders (Vogel and Marcotte, 2012; Perl et al., 2017; Kosti et al., 2016) (Figure 2). This makes studies involving the gene level resulting from bioinformatics analysis somewhat one-sided.

The process of TIME begins with the recognition of tumor-specific antigens by antigen-presenting cells, like dendritic cells, which capture and present these neoantigens to naïve T cells in lymph nodes, thereby initiating T-cell activation (Mellman et al., 2011). This activation triggers a series of immune responses, including the release of chemokines that attract more effector immune cells (such as CTLs, NK cells, and macrophages) to the tumor site, effectively infiltrating the tumor (Joyce and Fearon, 2015). Within the TIME, a pivotal change occurs as effector T cells reprogram immunosuppressive cells and alter the metabolic environment, diminishing the suppressive function of regulatory immune cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (Ho et al., 2015). This culminates in the direct cytotoxic attack on tumor cells by CTLs and NK cells, utilizing mechanisms like perforin and granzyme release to induce tumor cell apoptosis (Trapani and Smyth, 2002). Furthermore, some activated T cells differentiate into memory T cells, providing long-term surveillance and a rapid response mechanism against tumor recurrence (Sallusto et al., 2004) (Figure 3).

Recently, several scholars have dedicated their research efforts to understanding how paradoxical genes influence prognosis through the regulation of the TIME. Cao et al. analyzed data from TCGA and the gene expression omnibus, revealing that the expression of C-X-C motif chemokine ligand (CXCL)11 was elevated in colon cancer tissues compared to healthy tissues, and higher levels of CXCL11 correlated with improved survival outcomes (Cao et al., 2021). Furthermore, assessment of three independent datasets, including TCGA and two single-cell RNA sequencing datasets from Gene Expression Omnibus, in addition to immunohistochemistry data from a COAD patient cohort demonstrated that this tumor suppressor effect possibly due to its association with an increased presence of antitumor immune cells (CD8⁺ T cells, and CD56 NK cells), underscored CXCL11’s role in modulating the TIME (4). Furthermore, HERV-H LTR-associating 2 (HHLA2), a newly identified member of the B7 immune checkpoint family, is also a typical paradoxical gene (Yan et al., 2019). HHLA2 is minimally expressed in normal pancreatic tissues but shows significant upregulation from precancerous stages to invasive pancreatic ductal adenocarcinoma (PDAC), according to immunohistochemistry analyses on tissue microarrays (Yan et al., 2019). In 77.17% of PDAC cases, the expression of HHLA2 is strongly associated with an improved post-surgical prognosis, indicating functions of HHLA2 as a costimulatory ligand in pancreatic cancer, activating CD8⁺ T cell proliferation and improving patient prognosis (Yan et al., 2019). A subsequent study also presented a similar point; immunohistochemical analysis on tissue micro-arrays from surgically resected tumors of 122 pancreatic and 72 ampullary cancer patients revealed HHLA2 expression in 67% of pancreatic and 93% of ampullary tumors, associating enhanced expression with improved post-surgical outcomes, including delayed cancer recurrence and improved cancer-specific survival (Boor et al., 2020). Similarly, the study by Martinez-Turtos et al. highlights that overexpression of inositol-requiring enzyme 1α (IRE1α) in murine colorectal and Lewis lung carcinoma cells in syngeneic immunocompetent mice, leads to a tumor-suppressive phenotype (Martinez-Turtos et al., 2022). This anti-tumoral effect is attributed to the RNAse activity of IRE1α, which induces apoptosis in tumor cells, enhances adaptive anti-cancer immunosurveillance through XBP1 mRNA splicing, and regulates IRE1-dependent degradation of RNA (RIDD) (Martinez-Turtos et al., 2022). However, in addition to the tumor suppressive role of IRE1α, its tumor-promoting role is also evident in preclinical models of various cancers, including TNBC, PDAC, and colon cancer (Harnoss et al., 2020; Garcia-Carbonero et al., 2018; Xie et al., 2019). This duality suggests that the impact of Paradoxical genes on cancer prognosis may be multifaceted and not solely affected by the TIME (Figure 3).

Certain genes and their associated signaling pathways exhibit bidirectional effects on tumor prognosis, transitioning between inhibiting and promoting tumor progression. This dualistic behavior is also one of the key factor contributing to the emergence of paradoxical genes (Hanahan and Weinberg, 2011; Sadikovic et al., 2008). This biphasic regulatory effect can depend on various factors, including tumor stage, tumor-specific expression, and TME (Hanahan and Weinberg, 2011; Plaks et al., 2015; Gerlinger et al., 2012; Marusyk et al., 2012; Bray, 2016). The impact of gene expression can vary by cancer type and the tissue of origin (Stratton et al., 2009). Genes beneficial in one type of cancer might be deleterious in another (Vogelstein and Kinzler, 2004; Hanahan and Weinberg, 2011; Sadikovic et al., 2008). The role of E-cadherin in tumor suppression is well-established in BRCA due to its function in maintaining cell-cell adhesion and inhibiting metastasis (Padmanaban et al., 2019). However, in other cases, such as gastric cancer, the expression of can be associated with different outcomes based on additional factors like the presence of specific mutations or the overall state of cellular adhesion molecules (Becker et al., 1994). We focuses on signaling pathways with biphasic regulatory effects, including the TGFβ, NOTCH, and NF-κB pathways (Figure 4). Genes associated with these pathways are key contributors to the development of paradoxical genes, which exhibit peculiar behaviors during gene expression and regulation.

The expression of tumor suppressor genes exhibits significant variability across different cancer stages, contributing to the phenomenon of paradoxical genes (Sherr and McCormick, 2002). For instance, in the early stages of cancer, key genes like TP53 and RB1 play a crucial role in maintaining cellular integrity by regulating DNA damage repair and controlling cell cycle progression (Sherr and McCormick, 2002). However, as the tumor evolves, these genes often become inactivated due to mutations, deletions, or epigenetic modifications, leading to unchecked cell proliferation and advancement to more aggressive stages (Li et al., 1997; Cantley and Neel, 1999). PTEN, which regulates the PI3K/AKT signaling pathway, is commonly altered in cancers such as prostate and breast cancer, thereby facilitating tumor growth and survival (Li et al., 1997; Cantley and Neel, 1999; Salmena et al., 2008). In later stages, the suppression of tumor suppressor genes can precipitate metastasis and resistance to treatment, severely worsening the prognosis (Valastyan and Weinberg, 2011; Gottesman, 2002; Hanahan and Weinberg, 2000). Notably, the TGF-β pathway is recognized for its dual role in oncogenesis, acting as a tumor suppressor in initial stages while potentially fostering cancer progression in advanced stages (Massagué, 2008). Within this pathway, SMAD family members, including SMAD2 and SMAD4, are pivotal in relaying TGF-β signals that suppress cell division (Derynck and Zhang, 2003).

The TGFβ pathway suppresses tumors in the early stages of tumor development mainly by maintaining cellular homeostasis (including cell cycle arrest and apoptosis) and preventing uncontrolled cell proliferation (Colak and Ten Dijke, 2017). TGFβ regulates the cell cycle by inhibiting the transition from the G1 phase to the S phase, thereby preventing DNA replication and cell division, which is facilitated through the upregulation of cyclin-dependent kinase (CDK) inhibitors, which deactivate CDKs essential for cell cycle progression (Derynck, 1994; Decker et al., 2021). TGFβ also induces apoptosis, or programmed cell death through the activation of death-associated proteins and modulation of apoptosis-related genes, eliminating cells with potentially harmful mutations (Zhao et al., 2018; Schulte-Hermann et al., 1992). It also maintains cellular differentiation and proper morphology, thereby inhibiting the epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis (Hao et al., 2019). Furthermore, TGFβ exerts anti-inflammatory effects within the cellular environment, regulating immune cell activity and cytokine production to suppress chronic inflammation, thus preventing tumor growth (Viel et al., 2016; Coussens and Werb, 2002).

In advanced cancer, TGF-β primarily acts as a tumor promoter. TGFβ promotes the EMT, a critical process for metastasis, by regulating transcription factors like Snail, Slug, and Twist that modify adhesion and migration properties of the cell (Peng et al., 2022; Wang et al., 2013; Ang et al., 2023). Simultaneously, TGF-β exerts systemic immune suppression and inhibits host immunosurveillance and also regulates the infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the TME, causing direct changes in tumor cells (Yang et al., 2010). Neutralizing TGF-β enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses and increases the neutrophil-attracting chemokine production, leading to the recruitment and activation of neutrophils with an antitumor phenotype (Yang et al., 2010). It also interacts with cancer-associated fibroblasts and mesenchymal stem cells within the TME to remodel the extracellular matrix, increasing tumor stiffness and spreading cancer (Arima et al., 2023) (Figure 4).

The development of inhibitors that target TGFβ signaling is a promising treatment approach for cancers where TGFβ promotes tumor growth and metastasis (Derynck and Akhurst, 2007; Herbertz et al., 2015). These inhibitors generally block TGFβ receptors, preventing the downstream signaling cascades that lead to oncogenic effects (Herbertz et al., 2015). SB-431542 was initially identified as a potent and specific inhibitor of the activin receptor-like kinase (ALK)4, ALK5, and ALK7 type I receptors of the TGF-β superfamily, effectively and selectively inhibiting activin and TGF-β signaling without impacting BMP signaling or other divergent pathways like extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), or p38 mitogen activated protein kinase (Inman et al., 2002). In recent years, galunisertib (LY2157299 monohydrate), a selective, small molecule that can be taken orally to inhibit TGF-β receptor I kinase, exhibits antitumor activity across various cancer models, including breast, colon, lung, and HCC, by specifically downregulating SMAD2 phosphorylation and inhibiting the canonical TGF-β pathway (Herbertz et al., 2015). This drug is currently being evaluated in clinical trials in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) as part of monotherapy or in combination with other antitumor treatments to balance efficacy and safety, targeting cancers with high unmet medical needs like glioblastoma, pancreatic cancer, and HCC (Herbertz et al., 2015; Akhurst and Hata, 2012; Nadal et al., 2023). Clinical trials investigating combinations of TGFβ inhibitors with programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) inhibitors are exploring this approach, showing promising results in improving anti-tumor immunity and patient outcomes (Wrzesinski et al., 2007). Hence, understanding the tumor stage and the specific role of TGFβ is crucial to determining when and how to target this pathway effectively. Personalizing treatment based on the genetic and molecular profiles of individual tumors could optimize the efficacy of TGFβ inhibitors and minimize adverse effects.

The NOTCH signaling pathway is a crucial cell communication mechanism that influences various biological processes, such as differentiation, proliferation, apoptosis, and stem cell maintenance (Bray, 2016). This pathway involves NOTCH receptors (NOTCH1-4) interacting with delta-like (DLL1, DLL3, DLL4) or Jagged (JAG1, JAG2) ligands on adjacent cells, initiating proteolytic cleavages that release the NOTCH intracellular domain (NICD) (Bray, 2016). This domain moves to the nucleus, where it converts recombination signal binding protein for immunoglobulin kappa J region from a repressor to an activator, with mastermind-like proteins, initiating transcription of target genes families like HES and HEY (Bray, 2016). The finely tuned regulation of this pathway, which includes endocytic trafficking and post-translational modifications, is essential for maintaining cellular and tissue homeostasis (Fortini, 2009). The dual nature of NOTCH signalling in cancer biology—acting as a tumor suppressor in some contexts while promoting tumor progression in others—underscores the complexity of its signaling pathways and their diverse effects on cancer etiology and progression (Valdez and Xin, 2013) (Figure 4).

In specific cancers like those of skin and liver, NOTCH signaling is essential for maintaining cellular differentiation and tissue architecture (Panelos and Massi, 2009; Kawaguchi and Kaneko, 2021). Specifically, in squamous cell carcinoma, increased NOTCH signaling is associated with reduced tumor formation and progression (Panelos et al., 2008). Impaired NOTCH signaling, as demonstrated by the expression of the pan-NOTCH inhibitor dominant negative mastermind-like (DNMAML)1 in conditional transgenic mice, leads to hyperplastic epidermis and spontaneous development of cutaneous squamous cell carcinoma (SCC) and actinic keratoses, suggesting a protective role of canonical NOTCH signaling against cutaneous SCC (Proweller et al., 2006). Meanwhile, NOTCH1 signaling significantly inhibits the growth of HCC by inducing cell cycle arrest at the G (0)/G (1) phase and promoting apoptosis, by downregulating key cell cycle proteins and upregulating p21 and p53, while also suppressing antiapoptotic B-cell lymphoma 2(Bcl-2) expression (Giovannini et al., 2016; Giovannini et al., 2014; Kim et al., 2017; Qi et al., 2003; Viatour et al., 2011). However, the role of NOTCH signaling is paradoxically reversed in other types of cancers. In T-cell acute lymphoblastic leukemia (T-ALL) and certain breast cancers, NOTCH activation enhances cell proliferation, survival, and stemness, thereby promoting tumor growth and survival (Weng et al., 2004; Reedijk et al., 2005). Besides, the NOTCH signaling pathway also presents a biological dual nature widely in various cancers (Table 2).

The environmental sensitivity of suppressor genes refers to the fact that the expression and function of these genes are affected by the TME, including factors such as hypoxia and acidity, which in turn affects cancer progression and cellular behavior (Gatenby and Gillies, 2004; Webb et al., 2011). Additionally, immune cells within this microenvironment release a variety of cytokines and growth factors that significantly impact cancer dynamics (Coussens and Werb, 2002; Grivennikov et al., 2010; de Visser et al., 2006). Specifically, certain immune-derived factors may suppress tumor cells, while others might activate signaling pathways that induce tumor cells (Coussens and Werb, 2002; Grivennikov et al., 2010; de Visser et al., 2006). These regulatory effects of environmental sensitivity on tumor suppressor genes undoubtedly contributed to the emergence of paradoxical genes.

Traditionally, tumor suppressor genes such as TP53, retinoblastoma 1, and PTEN are well-known for their roles in regulating vital cellular processes, including DNA repair, cell cycle progression, and apoptosis (Salmena et al., 2008; Vogelstein et al., 2000; Kaelin, 1997). The TP53 gene, often described as the “guardian of the genome,” is implicated in nearly half of the occurrence of all human cancers due to its critical functions in DNA repair and cell cycle regulation (Vogelstein et al., 2000). Similarly, RB1 controls the G1/S transition in the cell cycle, and PTEN counteracts the PI3K/AKT signaling pathway to influence cell survival (Salmena et al., 2008; Kaelin, 1997). Typically, the loss of function in these genes, whether through mutations, deletions, or epigenetic alterations, lead to the uncontrolled cell growth that characterizes cancer (Salmena et al., 2008; Vogelstein et al., 2000; Kaelin, 1997).

Contrary to long-standing scientific beliefs that these genes are rarely overexpressed in tumor tissues, recent advancements and the continuous enrichment of gene network databases, including TCGA have confirmed that the potential overexpression of tumor suppressor genes in such tissues. This phenomenon may be influenced by variations in tumor mutational burden and the interplay between compensatory regulatory mechanisms and the tumor microenvironment. Tumors with high tumor mutational burden often exhibit increased genomic instability, which can lead to the upregulation of tumor suppressor genes as part of a compensatory response. This has been consistently demonstrated in database studies as well as in basic experimental research. This phenomenon has been consistently demonstrated through both database analyses and fundamental experimental studies. While many studies focus primarily on gene expression at the transcriptional level, neglecting the corresponding expression at the protein level can result in unbalanced and potentially biased interpretations of biological effects. Nonetheless, given that non-coding genes vastly outnumber coding genes, this imbalance is likely only a secondary factor contributing to the existence of contradictory genes. Moreover, as previously discussed, substantial evidence supports the notion that variations in pathway expression across distinct tissue environments underscore the presence of contradictory genes. Of particular relevance is the stage-specific expression of these genes. Notably, the overexpression of tumor suppressor genes frequently occurs during the early stages of tumorigenesis, functioning as part of the cellular response to oncogenic stress (Sakaguchi et al., 2003; Ohuchida et al., 2006; Braig et al., 2005; Brambilla et al., 1999). For instance, S100A11 has been identified as a paradoxical gene (Sakaguchi et al., 2003). Sakaguchi et al. demonstrated that S100C/A11 is a critical mediator of calcium-induced growth inhibition in human epidermal keratinocytes by facilitating the phosphorylation-induced nuclear translocation of S100C/A11, thereby halting cell growth (Sakaguchi et al., 2003). However, Ohuchida et al. investigated the expression of the tumor suppressor gene S100A11 across various stages of pancreatic carcinogenesis (Ohuchida et al., 2006). Their research revealed overexpression of S100A11 in the early stages of pancreatic cancer development, such as in intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasia (Ohuchida et al., 2006). However, its expression diminishes as the disease progresses advances (Ohuchida et al., 2006). Similarly, the overexpression of the tumor suppressor gene p16INK4a has been documented in early-stage tumors, where it has a crucial role in inducing cellular senescence and halting the proliferation of potentially cancerous cells (Braig et al., 2005; Brambilla et al., 1999). Similar studies not only confirm the existence of paradoxical genes but also emphasize their potential antagonistic effects on tumor progression during tumorigenesis. Paradoxical genes strive to maintain cellular homeostasis. As discussed in our previous work, this antagonistic effect may be linked to alterations in tumor metabolism, TIME, and related signaling pathways, suggesting a potential self-protective mechanism of the body against tumors. We propose that this might represent a form of intrinsic tumor suppression. This overexpression may arise from mechanisms such as subclonal heterogeneity or attempts to balance rapid proliferation and genomic instability. However, once this antagonistic equilibrium is disrupted, paradoxical genes may no longer be able to counteract the progression, leading to their diminished expression and the subsequent unchecked advancement of the tumor towards increased malignancy. Therefore, enhancing the expression of these tumor suppressor genes at early stages could offer promising potential for effective tumor treatment.

In summary, this review introduces the innovative concept of paradoxical genes, highlights the crucial role of tumor suppressor genes in targeted cancer therapy, and provides a theoretical framework for treating cancer by exploiting the balanced interplay between oncogenes and tumor suppressor genes.