Inevitably, therapeutic approaches to control tumor tissue without oncogene addiction, especially in the metastatic r/r stage, favor NOA targets that are genome-agnostic (Hendriks et al., 2023; Heudobler et al., 2024a). Some NOA targets have been shown to be the Achilles’ heel of metastatic neoplasia, as evidenced by pivotal therapeutic outcomes, e.g., with immune checkpoint inhibitors or engineered immunotherapies (Ye et al., 2025) (Table 2; Figure 2). However, therapeutic NOA inhibition can also orchestrate NOA-mediated stress responses in tumors and M-CRAC (Figure 1) (Hjaltelin et al., 2019). M-CRAC develops as an endogenous response to pulsed systemic tumor therapy triggered by the interaction of cancer cells with the adjacent tumor microenvironment (Barkley et al., 2022; Corsi et al., 2022). In addition, unintended off-target effects may limit the use of NOA-targeted therapies (Carneiro and El-Deiry, 2020).

The systematization of NOA protein tools is often based on specific aspects, such as the description of transcriptional, neuronal, stress response or clinically relevant NOAs (Nagel et al., 2016; Di Marco et al., 2024; Bradner et al., 2017). Schematic NOA classification systems fail to specify that NOA proteins are fully functional tools in transcriptionally regulated circuitries that can be reprogrammed, despite being transcriptionally addicted by oncogenic aberrations (Figure 2). Thus, by coping with cancer hallmarks and stress responses, NOA proteins remain communicatively linked to establish the tumor phenotype (Weinstein and Joe, 2008; Hjaltelin et al., 2019; Weinstein, 2002).

Comparative studies of tumor tissue editing therapies show that critical functions to “normalize” cancer hallmarks and tumor stress responses are preserved by the transcriptomic landscape of tumor tissue and can be regulatory restored by specific targeting of nuclear/cytokine receptor NOAs with receptor agonists that exploit reprogramming of the NOA tool available for cancer hallmarks and stress responses. M-CRAC, endogenous stress response and tumor tissue editing approaches reorganize NOA circuitries (Figures 1, 2) (Harrer et al., 2023b; Harrer et al., 2025).

A well-established systems pharmacological approach, the transcriptional reprogramming of hormone-dependent cancers with receptor antagonists, has now been complemented by a combined targeting of nuclear/cytokine receptors with receptor agonists to restore tumor tissue functions via the transcriptomes of tumor cell compartments on the background of a therapeutically stress-activated or epigenetically reprogrammed tumor tissue on basis of low-dose metronomic chemotherapy or epigenetic modelling, e.g., with azacitidine (Figure 2; Table 3).

For the establishment of network-based systems pharmacology to target tumor tissue addictions, the analysis of transcriptional regulators for NOA circuitries would be of central interest regarding how systems-therapeutically accessible cancer hallmarks and tumor stress responses, can be reprogrammed or deregulated to attack tumor viability and induce tumor cell death (Figure 1; Table 4).

A recurrent catalog of gene modules among tumors, correlated with recurrent cancer cell states, e.g., stress and interferon response or epithelial-mesenchymal transition, was identified that could explain therapeutically classifiable NOA circuitries dealing with cancer hallmarks/stress responses (Figure 3) (Barkley et al., 2022).

However, there is a lack of preclinical data on how cancer hallmarks and their activity profiles can be transcriptionally redirected for therapeutic purposes, how endogenous oncogene-addicted transcriptional control functions to maintain tumor tissue addictions, and which tumor-specific addictions to clustered stress responses/cancer hallmarks are transcriptionally targetable vulnerabilities (Figure 3) (Hjaltelin et al., 2019; Solimini et al., 2007).

Tumor tissue editing, as a systems pharmacology approach, has now pioneered the reprogramming of addicted transcriptome landscapes in tumor tissues by targeting selected receptor-induced transcription factor NOAs with receptor agonists to restore “normalized” NOA circuitries that resume activity among cancer hallmarks and stress responses by unleashing therapeutic phenotypic plasticity, differentiation, inflammation control, improved immune surveillance and pioglitazone-deregulated addictive energy metabolism, in patients with heavily pre-treated metastatic r/r neoplasias (Figure 3) (Gottfried et al., 2011).

In addition, individually edited NOAs have been identified as outcome-determining bottlenecks when targeted with the corresponding NOA inhibitor, e.g., everolimus (Figure 3) (Harrer et al., 2025).

The clinically observed reprogramming profiles of targeted cancer hallmarks refer to those hallmarks that are co-organized by tumor cells and neighboring stromal cells, i.e., inflammation control, enhancement of immune surveillance, addictive tumor metabolism, and therapeutic promotion of phenotypic plasticity, which is best explained by differentiation induction in r/r non-promyelocytic (non-PML) AML (Sibai et al., 2022; Heudobler et al., 2024a; Meier-Menches et al., 2022).

The primary systemic pharmacological goal of tumor tissue editing approaches is to gain access to retained and pharmacologically retrievable circuitries in cancer hallmarks and stress responses via synergistically linked activities of receptor agonist-induced transcription factors, in the context of therapeutically driven stress response and epigenetic modeling. As shown, nuclear/cytokine receptor agonists encounter classifiable clusters of tumor tissue addictions and deregulate/reprogram tumor stress responses/cancer hallmarks via NOAs and NOA circuitries (Figure 4).

Therapeutic agonists of receptor-induced transcription factor NOAs target the same nuclear/cytokine receptors that oncogene addictions use to maintain tumor phenotypes. Reprogramming with receptor agonists results in measurable changes in cancer hallmarks and tumor identity, tumor cell death, and long-term tumor control of r/r hematologic neoplasms, cancers, and sarcomas (Figure 4) (Zhao and Iyengar, 2012; Harrer et al., 2025; Heudobler et al., 2018b; Nogales et al., 2022).

Non-PML AML, treated via non-oncogene addiction targets, can be used as a model to distinguish between AML plasticity that is therapeutically exploited, and therapeutically mediated AML plasticity that is induced by systemic AML therapies leading to drug resistance, e.g., to azacitidine (Heudobler et al., 2024a; Thomas et al., 2015; Kattner et al., 2020; Heudobler et al., 2018a).

In all three studied AML patients who developed azacitidine resistance during the immediate azacitidine monotherapy, resistance could be overcome by triple transcriptional modulation involving pioglitazone and ATRA, as indicated by CR induction in two patients and objective response in one patient (Heudobler et al., 2024a; Thomas et al., 2015; Heudobler et al., 2018a; Kattner et al., 2020). Triple transcriptional modulation plus azacitidine reprograms tumor-promoting hallmarks via differentiation induction and inflammation control by implementing reciprocal activity in NOA driven circuitries. The similar resistance resolving phenomenon has been observed in cases of IMiD resistance in multiple myeloma and imatinib failure to induce complete molecular remission in CML (Figure 1) (Heudobler et al., 2019a; Rousselot et al., 2017; Prost et al., 2015).

Receptor NOAs have established a transcriptional-based systems coherence, maintenance and reprogramming capabilities of NOA circuitries, thereby covering cancer hallmarks/tumor stress responses, as summarized by the following clinical observations: (1) Tumor tissue editing has therapeutically unlocked the tumor phenotypes by targeted reprogramming of cancer hallmarks with distinct combinations of nuclear/cytokine receptor agonists (Figure 4). (2) The 15 phase I/II studies demonstrate that selected, highly specific recombinations of receptor-triggered transcriptional modulators are necessary for reprogramming distinct patterns of cancer hallmarks (Table 3). (3) Nuclear/cytokine receptor agonists induce pivotal tumor responses up to CR and cCR in r/r neoplasms. (4) Tumor tissue editing resolves or attenuates M-CRAC in metastatic r/r neoplasia (Figure 1).

M-CRAC further illustrates that the NOA proteome is endogenously cross-linked by transcriptional programs that can be severely challenged and adapted via stress responses to pulsed systemic therapies (Hjaltelin et al., 2019; Harrer et al., 2023b). Endogenously transcriptionally regulated clustered NOA circuitries of cancer hallmarks and tumor stress responses implement timely tumor stress relief, even in response to severe therapy-induced stress, to rescue tumor viability (Figure 1).

Upon systemic pulsed tumor therapy, tumor stress responses are uniquely rewired across different tumor histologies to organize sufficient tumor stress relief (Hjaltelin et al., 2019). Thus, histologically different types of cancer may have stress-activated mechanisms in common, while stress responses may be differentially organized (Hjaltelin et al., 2019).

Tumor tissue editing as a targeted, metronomic, transcription-modifying therapy is characterized by the ability to prevent sufficient stress relief in tumor tissue and to reprogram cell-type specific regulatory circuitries within transcriptionally targeted cancer hallmarks (Figure 4). Thus, tumor tissue editing leads to profound changes in tumor tissue identity and homeostatic balance. The directly clinically observed reprogrammed cancer hallmarks were inflammation control, enhanced immune surveillance, and differentiation (Table 4) (Papi et al., 2014; Glass and Ogawa, 2006; Dicitore et al., 2014; Klobuch et al., 2018; Tilg et al., 1995; Senft and Ronai, 2016; Reichle, 2010; Bradner et al., 2017; Heudobler et al., 2024a; Heudobler et al., 2024b; Vogt et al., 2006; Lüke et al., 2021).

Previous NOA classifications have failed to highlight large-scale receptor-induced transcription factors that have emerged as targetable NOAs, dramatically altering NOA circuitries and therapeutically unlocking tumor phenotypes (Figure 4).

Targeting selected clusters of receptor NOAs involved in vulnerable tumor tissue addictions with drugs that have little or no monoactivity, but regulatory synergistic activity, is sufficient to reprogram cancer hallmarks, deregulate tumor stress responses, and edit individual NOAs for therapeutic purposes (Figures 1, 2; Table 3). In the presented studies, the configuration of selected cancer hallmarks available for transcriptional reprogramming is decisively supported by the adjacent cancer microenvironment, i.e., inflammation, immune response, tumor metabolism, energy metabolism and uncontrolled proliferation (Table 3) (Sibai et al., 2022; Heudobler et al., 2024a; Lüke et al., 2021; Harrer et al., 2022; Reichle et al., 2007a; Reichle et al., 2007b; Vogt et al., 2003; Walter et al., 2017; Reichle et al., 2010; Reichle et al., 2009; Hau et al., 2007; Heudobler et al., 2021; Heudobler et al., 2019a; Walter et al., 2010; Heudobler et al., 2018b; Hart et al., 2015; Vogelhuber et al., 2015).

Metronomic (very) low dose chemotherapy or epigenetic regulation, e.g., with azacitidine in non-PML AML, are essential activators of clinically relevant transcriptional modulation (Tables 3 and 4; Figure 3) (Harrer et al., 2023b). Targeting receptor-driven transcriptional regulators without metronomic low dose chemotherapy or azacitidine is ineffective in the setting of metastatic r/r neoplasia (Table 3). Tumor tissue editing reassigns low dose metronomic chemotherapy to a completely novel task, namely, to induce stress responses in tumor tissues. The choice of cytotoxic agent seems to play a minor role in extremely low dose metronomic chemotherapy. Among the alkylating agents, trofosfamide and treosulfan are less emetogenic than cyclophosphamide (Harrer et al., 2023b).

The known biological activities of the nuclear/cytokine receptor agonists used are indicative of broad reprogramming and deregulatory activities (Heudobler et al., 2024b). The transcriptomic landscapes in tumor cell compartments that operate tumor-specific tissue addictions, as shown, retain unlockable reprogramming profiles of cancer hallmarks.

Cyclooxygenase-2 (COX-2) inhibitors synergize with pioglitazone, contribute to NOA editing in r/r HL and does not augment clinical activity of interferon-α in r/r RCCC (Gehrmann et al., 2004; Schwandt et al., 2011; Harrer et al., 2025). The clinical effect of COX-2 inhibitors in many schedules seems to be supporting, as pioglitazone is the outcome determining substance in a randomized trial metronomic chemotherapy and COX-2 inhibitor plus/minus pioglitazone in metastatic r/r melanoma and the combination of receptor agonists used for tumor tissue editing classifies the editing of NOA circuitries coping with cancer hallmarks (Reichle et al., 2007b; Zelenay et al., 2015; Chan et al., 2007; Yang et al., 2025; Harrer et al., 2023b).

Known patterns of response to metronomic low-dose chemotherapy add important biological effects (Cornice et al., 2024; Heudobler et al., 2018b) (Figure 5). Metronomic chemotherapy and low-dose azacitidine have well-studied pleiotropic activity profiles, including a T-cell-specific immune response in animal models and “jump-starting” activity in tumor tissue editing trials (Figure 4) (Ge et al., 2012; Harrer et al., 2023b). A continuous tumor stress response is necessary to facilitate the “jump-start” of the tumor systems’ transcriptional editing (Lüke et al., 2022). Intolerance to very low doses of metronomic chemotherapy was an exclusion criterion in all studies, as transcription modulation is ineffective without mild “cytotoxicity” as a backup. The same applies to the combination of transcriptional modulators with targeted therapies (Ben-Yishay et al., 2024; Prost et al., 2015; Plumber et al., 2024; Heudobler et al., 2019a).

In rare cases, clinically relevant off-target transcriptional effects occurred. In less than 5% of patients, therapy had to be discontinued due to the tumor tissue editing approach used. These favorable toxicity data were due to scheduled dose reductions for metronomic chemotherapy and the reduced frontline dose of azacitidine in AML, compared to the approved standard dose (Heudobler et al., 2024a). Scheduled dose reductions were used if off-target effects upon transcriptional modulation or chemotoxicity occurred. Pioglitazone may induce edema, which is dose-dependent in most patients, and may lower blood glucose levels in diabetic patients, necessitating adjustments to antidiabetic therapy. COX-2 inhibitors plus pioglitazone may induce mild renal insufficiency, which can be alleviated by discontinuing the COX-2 inhibitor. Interferon-α was primarily used at a low dose. Thus, interferon-α did not have to be discontinued due to neurological or psychiatric problems (Harrer et al., 2023b).

Off-target effects of classic targeted therapies, such as mTOR inhibitors have to be considered, e.g., pneumonitis following mTOR inhibition with everolimus (n = 1 patient with Hodgkin’s lymphoma) (Harrer et al., 2025).

The combinations of agonists targeting receptor-triggered transcription factors have been chosen on the basis of their mostly modest but well-known clinical activity: interferon-α has activity at high doses in renal clear cell carcinoma (RCCC), everolimus in Hodgkin’s lymphoma and glucocorticoids in hematological neoplasms (Aldin et al., 2023; Guarini et al., 2012; Qualls et al., 2025). Pioglitazone is the connecting link, as peroxisome proliferator-activated receptor (PPAR) agonists are frequently expressed in malignant cells, particularly in metastatic diseases (Reichle 2010). Tumor proteomic profiling has not yet been systematically performed with respect to receptor-triggered transcription factors and corresponding down-stream transcription factors. Proteomic platforms, as shown, can be used to test, e.g., for AML “normalization,” e.g., differentiation in vitro (Meier-Menches et al., 2022).

To differentially target inflammation addiction the following receptor combinations were selected for dual/triple transcriptional modulation with the PPARα/γ agonist pioglitazone, PPARα/γ/glucocorticoid receptor agonists or PPARα/γ/interferon-α receptor agonists (Table 3).

The use of cancer hallmarks that are co-regulated by the microenvironment as targetable tumor tissue addictions offers important advantages. Microenvironment-targeted tumor cell behaviors can be transcriptionally deregulated in critical ways, while stromal conditions can be stimulated to prevent tumor cell growth (Xiao et al., 2024; Hendrix et al., 2007; Sibai et al., 2022; Ge et al., 2012). Even metastatic tumors conditioned with M-CRAC that are refractory or recurrent can be sufficiently targeted by therapeutically involving tumor and stromal cells to be controlled in the long term (Vitale et al., 2019; Harrer et al., 2023b).

Tumor tissue editing approaches also successfully use the metronomic principle for the application of receptor-triggered transcription factor agonists. The large-scale configuration of clustering tumor tissue addictions determines the respective therapeutically suitable recombination of receptor agonists (Table 3).

Inflammation as a hallmark of cancer is transcriptionally accessible differently depending on the type of inflammatory addiction, either with pioglitazone alone as a PPARα/γ agonist (angiosarcoma, melanoma, glioblastoma, cholangiocellular carcinoma, hepatocellular carcinoma and gastric cancer) (Vogt et al., 2003; Reichle et al., 2007b; Hau et al., 2007; Walter et al., 2017; Reichle, 2010; Reichle et al., 2010; Reichle et al., 2009) or in the combination pioglitazone/interferon-α [renal clear cell carcinoma, multisystem Langerhans cell histiocytosis (mLCH)] (Reichle et al., 2007a; Harrer et al., 2022), or pioglitazone/dexamethasone in mLCH, multiple myeloma (MM), castration-resistant prostate cancer (CRPC) (Harrer et al., 2022; Heudobler et al., 2019a; Vogelhuber et al., 2015; Walter et al., 2010; Hart et al., 2015; Prins et al., 2012), and pioglitazone/dexamethasone/everolimus in r/r Hodgkin’s lymphoma (HL) (Lüke et al., 2021; Harrer et al., 2025).

Measurement of serum C-reactive protein (CRP) in HL, renal clear cell carcinoma (RCCC), mLCH, and melanoma served as a follow-up marker of inflammatory response. CRP response correlated well with tumor shrinkage, but shrinkage was delayed in r/r RCCC (Hoefflin et al., 2020; Reichle et al., 2007a; Lüke et al., 2021; Harrer et al., 2022; Reichle et al., 2007b; Reichle and Vogt, 2008).

The combination of pioglitazone and all trans-retinoic acid is characterized by a strong differentiation induction in non-PML AML, even in AML with a complex aberrant karyotype but also in muscle invasive bladder cancer in animal models (Heudobler et al., 2024a; Thomas et al., 2015; Plumber et al., 2024).

Qualitatively completely different activity patterns depending on the respective co-modulator of pioglitazone, RAR, glucocorticoid receptor or interferon-alpha receptor are probably the reason that these receptors have not yet appeared as NOAs. Their clinically relevant interactions and the possibility of combinatorial specification of their activity profiles are therapeutically crucial for r/r metastatic neoplasias (Table 3).

NOA addiction circuitries have been clinically identified as potential targets for NOA systems pharmacology. These NOA systems circuitries are suggested to mediate clinical response to NOA-targeted systems pharmacological approaches.

However, given that NOA addiction circuitries are modular in nature, the definition of circuitries does not imply that identical systems pharmacologic approaches will target identical circuitries. Identical transcriptional modulators, such as pioglitazone, used within systems pharmacology approaches, induce an objective response or continuous complete remission (cCR) via differential biological effects affecting tumor-associated inflammation, immunosurveillance, differentiation and tumor metabolism (Harrer et al., 2023a). Furthermore, in animal models, pioglitazone contributes to the induction of unexpected biological outcomes, such as fatty degeneration of tumor cells or tumor stem cell toxicity, depending on the combination partners (MEK inhibitors or imatinib) (Prost et al., 2015; Ishay-Ronen and Christofori, 2019).

Modular NOA-directed therapy is characterized by the extent to which NOA circuitries that maintain hallmarks of cancer, stress responses and M-CRAC can be separated and recombined therapeutically by tumor tissue editing approaches for finally disrupting tumor resilience and viability (Figures 1, 3). Thus, tissue editing approaches reveal a wide range of potential systems pharmacology approaches involving NOAs, which remain largely unexplored.

Therapeutic modeling of addicted tumor systems with editing approaches is multi-faceted and far-reaching, as the therapeutic approach spans multiple biological scales, from molecular interactions to cell behavior to communicative tissue architecture/ecology (Sibai et al., 2022) (Figures 1, 3).

Tumor microenvironments provide histology-specific NOAs. These NOAs are communicatively integrated into hardwired NOA circuitries, as stromal NOA patterns can even characterize histological tumor subtypes (Lenz et al., 2008). Thus, NOA proteins are typically distributed in all cellular tumor compartments and are characteristically organized to maintain stroma coregulated cancer hallmarks (Solimini et al., 2007).

Tumor tissue editing involves three therapeutically relevant NOA levels that provide information about cancers’ addictive traits (Figure 3).

The transcriptionally targeted NOA proteome copes with tumor stress responses and cancer hallmarks (Figure 3) (Di Marco et al., 2024). In addition, NOAs are also present within the organ invasive front of tumors (Tetzlaff et al., 2025; Jeong et al., 2025; Chastney et al., 2025; Blazquez et al., 2022).

The clinical observations of inflammation control and reprogramming of the stroma coregulated cancer hallmarks (improved immune response) in metastatic r/r neoplasias reveal that tightly structured inflammation-associated NOA circuitries regulate tumor-associated inflammation in a classifiable manner, across cellular tumor compartments and independent of tumor type, via receptor-induced transcription modulation (Table 3).

Clinical data on the reprogramming of tumor-promoting hallmarks, with the potential for consecutive complete response (CR) and cCR induction in highly heterogeneous tumor histologies, supports the pharmacological possibility of comprehensively reorganizing NOA circuitries across histologically highly different tumor tissues in a modular manner. This is achieved using NOA-based systems pharmacology approaches, which include agonists of receptor-triggered transcription factors such as peroxisome proliferator-activated receptors (PPARα and γ), interferon (IFN)-α, retinoid receptors (RAR), and the glucocorticoid receptor (Figures 2, 4).

Specific transcriptional approaches, epigenetic (azacitidine) and tumor stress promoting mechanisms are the basis for substantial reprogramming of NOA based circuitries, a process that can be easily cytologically visualized in AML. In non-PML AML, neutrophils harboring acquired genetic aberrations in the blasts can be detected following successful differentiation inducing NOA triggered therapy (Thomas et al., 2015).

Furthermore, a steep serum CRP response in a series of quite different neoplasias may precede continuous complete remission, suggesting that NFκB is a central target of the therapeutically used transcriptional modulators (Reichle et al., 2007a). A little-known phenomenon of interferon-α is its massive CRP-suppressive activity in healthy individuals (Tilg et al., 1995).

Figure 4 highlights transcriptional regulators targeted by receptor-triggered pathways, the PI3K-AKT-mTOR and the PPARγ/PTEN/Akt axes and the MAPK/ERK pathway (Glaviano et al., 2023).

Potential transcriptionally accessible NOA targets operating in NOA circuitries to control inflammation could be NF-kB, IL-6, COX-2, STAT3, VEGF and corresponding receptors (VEGFRs), HSP70/HSP90, mTOR, downregulated PTEN, general tumor-associated stress responses and NOAs in stromal cells (Zheng et al., 2013; Teresi and Waite, 2008; Harrer et al., 2023a; Spella et al., 2023; Petroni et al., 2022).

The central regulation of the mTOR pathway by tumor tissue stress responses and the counterregulation by tumor tissue editing has been summarized in the context of NOA based editing therapy in r/r Hodgkin’s lymphomas (Harrer et al., 2025).

Oncogenic aberrations only define the (common) inflammatory addiction phenotype, and thus the specific transcriptional accessibility. However, the oncogenic background does not affect the fundamental possibility of accessing NOA circuitries integrated in cancer hallmarks via tumor tissue editing techniques.

These findings greatly simplify the therapeutic targeting of cancer hallmarks using systems pharmacology approaches. However, the system-relevant molecular mechanisms remain to be elucidated.

In the future, diagnostics on circuitries that maintain NOA addiction and corresponding regulatory transcription factors will have a tremendous impact on the design of systems pharmacological therapy approaches with tumor tissue editing techniques.

Considering the histological and genomic diversity of recurrent and refractory metastatic neoplasias included in multiple clinical trials (Table 3), as well as the unique responses to NOA-based tumor tissue editing approaches ranging from long-term tumor control, objective response, CR to cCR, it appears that NOA circuitries are accessible across many different histological tumor types. However, the design of tumor tissue editing approaches must be adapted to the NOA circuitries and their modular links, as shown for r/r RCCC and mLCH (Table 3).

Gastric cancer was the only histology that did not significantly respond to pioglitazone in a randomized phase II trial among 15 different trials for highly varying tumor histologies, including cancers, sarcomas, and hematological neoplasias. Gastric cancer cells express PPARγ (Ezzeddini et al., 2021; Reichle, 2010). This suggests that modular circuitries may be resistant to PPARγ agonists in gastric cancer. The principal possibility of successfully adapting transcriptionally active combination therapies in a genome-agnostic way gives rise to the hope that differential combinations of agonists of receptor-triggered transcription factors may solve the gastric cancer problem.

Complete remissions could not be observed in r/r high-grade gliomas, hepatocellular carcinomas (one clinical remission histologically not confirmed), gastric cancer or NSCLC (Table 3). For using tumor tissue editing approaches as template for overcoming M-CRAC, NOA circuitries have to be studied in detail on a molecular basis.

In analogy to oncogenic events, the editing process transcriptionally reorganizes and substantially reprograms cancer hallmarks, stress responses and leads to novel protein-protein interactions, altered pathway activities, stromal composition and tumor-stroma interactions (Li et al., 2023; Reichle, 2013; Heudobler et al., 2024a; Thomas et al., 2015; Heudobler et al., 2018b; Califano, 2011; Reichle and Hildebrandt, 2009; Hjaltelin et al., 2019) (Table 3; Figure 1).

Thus, breaking the tumor tissue addictions with editing approaches, as shown in many tumor types, r/r cancers, sarcomas and hematological neoplasms, is accompanied by crucial changes in the cancer phenotype (Harrer et al., 2025; Heudobler et al., 2024a; Harrer et al., 2025; Harrer et al., 2022; Reichle et al., 2007a) (Table 5).

Transcriptional interventions in the context of tumor stress response and cancer hallmarks always involve multiple hallmark activities simultaneously, beyond those clinically observed (Table 4). Due to the “multi-tasking” activity profiles of transcriptionally active, editing agents, hallmarks with stromal involvement - inflammation, immune response, angiogenesis, invasion and metastasis, release of phenotypic plasticity, sustained proliferative signaling, and deregulation of cellular energetics - are simultaneously addressed (Harrer et al., 2023a; Sibai et al., 2022).

From a tissue processing perspective, it does not seem to matter much that hallmark activities are heterogeneous within tumors. Agonist combinations may be adapted respectively, to oncogenic altered hallmark addictions (Sibai et al., 2022; Harrer et al., 2025; Harrer et al., 2022).

Clinically successful reprogramming of NOA circuitries that configure cancer hallmarks is best evidenced by CR and cCR induction in r/r non-PML AML, HL, mLCH, RCCC, angiosarcoma, cholangiocellular carcinoma, and melanoma (Table 3) (Reichle et al., 2007a; Ugocsai et al., 2016; Vogt et al., 2006; Lüke et al., 2021). Differentiation induction of leukemic blasts to neutrophils changes the identity of AML tissue. The genome-agnostic activity of tissue editing is at best demonstrated in AML: complex aberrant cytogenetics does not exclude differentiation induction and CR (Klobuch et al., 2018; Heudobler et al., 2024a; Heudobler et al., 2018a; Thomas et al., 2015). CR after tumor tissue editing could be successfully consolidated with allogeneic blood stem cell transplantation in r/r AML, or relapses after allogeneic blood stem cell transplantation could be rescued in r/r HL and AML (Kattner et al., 2020; Heudobler et al., 2024a; Lüke et al., 2021).

Although, NOA circuitries connect oncogenic drivers at different tumor tissue levels, NOA circuitries provide an autonomous transcriptionally accessible target (Li et al., 2023) (Table 5). The ability of specifically selected agonist combinations of nuclear/cytokine receptors to reprogram cancer hallmarks, to deregulate stress responses or to target NOAs as therapeutically relevant bottlenecks impressively demonstrates that NOAs are organized in transcriptionally hardwired NOA circuitries (Ma and Kroemer, 2024; Kusaczuk et al., 2024).

Tumor-associated inflammation plays a critical cross-cancer role in the promotion of tumor growth and M-CRAC (Harrer et al., 2023b; Sibai et al., 2022). Inflammation-associated serum biomarkers, such as CRP, facilitate the identification of tumor-associated inflammation as an important cancer hallmark with strong activity in histologically diverse tumor types, particularly in advanced disease, and allow us to empirically specify potential nuclear/cytokine receptor agonist combinations (Table 3) (Hart et al., 2020).

Suppression of inflammation and therapy-induced stress responses in tumor tissue with receptor agonists directly affects additional stroma-coregulated cancer hallmarks, immunosurveillance, angiogenesis, extracellular matrix, tumor proliferation and M-CRAC (Sibai et al., 2022; Harrer et al., 2023b).

An important finding from the comparative analysis of tumor tissue editing data in metastatic r/r neoplasms is that histologically/genetically quite different tumors provide unique differential transcriptional access to their transcriptional landscape to reconfigure NOA circuitries that support tumor-associated inflammation and other stroma coregulated hallmarks, although tumor-associated inflammation, e.g., is profoundly differentially integrated in the tumor context in r/r mLCH and r/r RCCC, but outcome to pioglitazone/interferon-α with cCR may be identical (Table 3; Figure 6). A key difference in inflammation management between r/r mLCH and r/r RCCC is evident by the fact that RCCC cells directly release CRP into the serum, in addition to indirect CRP secreted by the liver (Jabs et al., 2005).

Pioglitazone is the common transcriptionally active ligand contributing to inflammation control in all presented editing trials, although experimental data demonstrate the extremely heterogeneous implementation of neoplasia-associated inflammation as a cancer hallmark (Jong et al., 2024). CR or cCR in quite different metastatic r/r neoplasias after selective reprogramming of tumor-associated inflammation supports the availability of ubiquitous, cross-tumor histology targetable transcriptional programs constituting classifiable NOA circuitries susceptible to pioglitazone plus/minus transcriptionally active combination partners (Table 4; Figure 4) (Hjaltelin et al., 2019; Harrer et al., 2022; Reichle et al., 2007a) (Figure 1; Table 3). These clinical observations were not predicted by current experimental data (Hjaltelin et al., 2019; Luo et al., 2009; Vervoort et al., 2022; Harrer et al., 2023b).

The clinical data on the transcriptional processing of inflammation indicate that NOA circuitries associated with the hallmark inflammation represent important systems pharmacological targets for rescuing metastatic r/r neoplasias: the specificity of dual/triple transcriptional modulation targeting different transcriptionally regulated NOA circuitries is best illustrated in metastatic r/r neoplasias responding with CR and cCR, even if edited NOAs must be additionally targeted to achieve cCR, as shown for r/r HL (Table 4; Figure 7) (Reichle et al., 2007a; Harrer et al., 2022).

At least two different clusters of transcriptionally regulated NOA circuitries may be attributed to mLCH histology with respect to the hallmark inflammation, one responding to pioglitazone/dexamethasone with cCR, the other to pioglitazone/interferon-α (Figure 7) (Reichle et al., 2007a; Harrer et al., 2022).

Pioglitazone/interferon-α rescues pioglitazone/dexamethasone failure, even in the setting of disease-related bone marrow and liver failure (Harrer et al., 2022). The reason for a change of transcription modulators is probably quite clear. Addiction spans multiple biological scales, and thus, in the case of mLCH-associated liver and bone marrow failure, a maximized anti-inflammatory effect combined with interferon-α-linked immune modulation was significantly more effective (Harrer et al., 2022). The case highlights that tumor addiction involves not only addictions of the tumor tissue itself, but also reactions between tumor and host. This means that differential access to histologically identical neoplasms may also depend on the host-tumor interface.

Only after the addition of low-dose interferon-α to pioglitazone in a second study in metastatic r/r RCCC did objective responses occur and consecutive CR and cCR (Tupikowski et al., 2015; Reichle et al., 2007a). Outcome data in metastatic r/r RCCC suggest that more than one RCCC editing approach leads to cure, as few CRs were converted to long-term cCRs (two out of four CRs) as in angiosarcoma and cholangiocellular sarcoma, while two editing approaches were defined in mLCH (Reichle et al., 2007a). Heterogeneous long-term responses in r/r RCCC could be due to the absence of gp160 expression, a protein that mediates anti-tumor IFN responses, or RCCC subclones have a large genetic distance (Nanus et al., 1990; Sibai et al., 2022). In addition to the direct anti-tumor activity of interferon-I, it enhances CTL effector function via STAT3-activated granzyme B expression (Lu et al., 2019). Therefore, in the future, diagnosis of tumor tissue addiction-specific configuration dynamics of tumor-associated inflammation, likely including host responses, would provide a framework for pre-therapeutic optimization of tumor tissue editing schedules (Jong et al., 2024).

Pioglitazone/dexamethasone combination induces long-term cCR, CR, PR associated with long-term disease stabilization, by reprogramming tumor-associated inflammation and resolving or attenuating M-CRAC in multiple myeloma (MM), castration-resistant prostate cancer (CRPC) or r/r mLCH (Vogelhuber et al., 2015; Heudobler et al., 2019a; Harrer et al., 2023b). Thus, completely different histologies share, at least in part, clustering system vulnerabilities.

From a conceptual standpoint, NOA-based systems pharmacology is found on observations from randomized phase II and phase I/II trials (Table 4).

AML studies clearly demonstrate that significant clinical responses can be achieved using identical systems pharmacology approaches in genetically and molecularly highly heterogeneous AMLs (Heudobler et al., 2024a). Furthermore, genetic heterogeneity can be inferred from preceding mixed responses to targeted therapies. The consecutive achievement of continuous complete remissions with NOA-based systems therapy suggests that intratumoral genetic heterogeneity can be overcome, thereby again emphasizing the genome-agnostic approach.

We categorized NOA-based systems pharmacological approaches also as genome-agnostic if underlying tumor cell genetics were unknown but the histologies differed significantly, as in the case of r/r mLCH and r/r RCCC, but identical tumor tissue editing approaches induced cCR (Tabe 1; Figure 6).

One reason for the successful application of tumor tissue editing approaches is the genome agnostic activity of NOA based therapies in r/r metastatic neoplasias. The simultaneous targeting of NOAs in tumor and adjacent stromal cells facilitate major reprogramming of tumor-promoting hallmarks. Major tumor promoting hallmarks, inflammation, immunosurveillance, differentiation and tumor cell metabolism are constituted by cells of the tumor compartment, regardless of whether they are genetically altered or genetically normal but actively contributing to malignant behavior.

Therefore, editing therapies fulfill key therapeutic requirements to induce CR (in three tumor types) and cCR (in an additional five tumor types), even in seemingly incurable metastatic r/r neoplasms (Figure 6). The use of genome-independent tumor tissue editing approaches allows us to successfully tailor nuclear/cytokine receptor agonists to the specific addiction clusters (Reichle et al., 2007a; Harrer et al., 2022).

The addition of pioglitazone to metronomic chemotherapy in gastric cancer did not add any clinical benefit despite the involvement of PPARγ in the pathogenesis of gastric cancer (randomized phase II study) (Ezzeddini et al., 2021; Reichle et al., 2009). In high-grade gliomas only stabilization of disease was possible, while in hepatocellular carcinoma and NSCLC the best response was partial remission (PR) (Hau et al., 2007; Heudobler et al., 2021; Walter et al., 2017). As CR or cCR has been achieved in all other neoplasms, it is expected that the combination of receptor agonists in NSCLC, hepatocellular carcinoma and high-grade glioma can be optimized by adding pioglitazone and a third receptor agonist. In gastric cancer, novel receptor agonist combinations should be selected. Therefore, a classification of the respective regulatory NOA circuitries is not possible with the available outcome data (Table 5).

Transcriptionally regulated NOA circuitries can currently be classified according to the combination of receptor-triggered transcription factors targeted with receptor agonists, a systems pharmacological classification, or according to the stromal coregulated cancer hallmarks that are reprogrammed if CR or cCR can be achieved in principle, in a study cohort with metastatic r/r neoplasia (Luo et al., 2009) (Figures 2, 7). The possibility of a systems pharmacological tumor classification shows that pathways, cancer hallmarks and stress responses are similar in different tumor types, although each tumor can be classified as an individual tumor considering genetic alterations (Vogelstein et al., 2013).

Only a few neoplasms can be cured in the metastatic stage with oncogene-addicted targets, e.g., in Philadelphia-positive chronic myeloid leukemia, ALK-positive neoplasms, neoplasms with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) neoplasias due to excellent sensitivity to immune checkpoint inhibitors or CRs may be achieved with neurotrophic tyrosine kinase (NTRK) inhibitors in basket trials for pediatric and adult solid tumors with NTRK fusion (Thein et al., 2024; Yılmaz et al., 2024).

Genetic heterogeneity occurs primarily at metastatic sites, with additional transcriptional heterogeneity among neoplastic cells, organized into cancer cell states as a general characteristic of tumor tissue (Barkley et al., 2022; MacDonald et al., 2025).

The systematic control of metastatic r/r neoplasias without distinct oncogenic drivers by tumor tissue editing demonstrates that beyond cell-autonomous regulatory programs, classifiable large-scale communicatively linked transcriptional NOA circuitries, including the tumor stroma, are available at metastatic tumor sites and can be transcriptionally reprogrammed, importantly independent of genetic or transcriptional heterogeneity at metastatic sites. The evidence is CR and cCR across quite different neoplasias in the metastatic r/r stage in response to the concerted attack of the systems pharmacological approach, tumor tissue editing (Chen et al., 2024; Harrer et al., 2023b) (Table 5).

Targeting individual NOA proteins faces three major therapeutic obstacles. (1) Individual NOA targets at metastatic sites prove to be heterogeneous like oncogenic aberrations and are therefore a major cause of treatment failure (Dagogo-Jack and Shaw, 2018). (2) Long-term tumor control is often limited, and (3) the induction of M-CRAC as a result of therapy-induced tumor stress responses is almost obligatory. Despite the successful use of NOA targets in metastatic r/r neoplasia, palliation remains the main therapeutic perspective (Chang et al., 2021; Hendriks et al., 2023).

Tumor tissue editing techniques take effective measures to treat metastatic r/r neoplasms by viewing NOAs as communicatively connected circuitries to establish new therapeutically relevant homeostatic equilibria.

A diagnostic problem is to uncover transcription factors that maintain hardwired NOA circuitries in cancer hallmarks and tumor stress responses for targeted reprogramming (Tao and Wu, 2023). Nuclear/cytokine receptors evade routine detection as NOAs and are distributed in all tumor cell compartments. Currently, only selective NOA proteins are studied in front-line diagnostics (Di Marco et al., 2024; Meyer et al., 2010; Hendriks et al., 2023).

Critical points for targeting NOA circuitries are the appropriate selection of combinations of nuclear/cytokine receptors and their selected on-topic activity in large-scale communicative circuitries of tumor tissue addictions. An experimentally less appreciated phenomenon is the co-regulatory activity profile of combined transcriptional modulation in the context of tumor systems, in particular, how the multifunctionality of NOA targets can be focused and edited, such as mTOR (Harrer et al., 2025).

Selection of the study population most likely to benefit from a particular tumor tissue editing approach is not possible, as NOA circuitries and the corresponding transcriptional profile have yet to be defined for individual patients (Meier-Menches et al., 2022; Heudobler et al., 2024a).

Since editing therapies are genome-agnostic, genetic heterogeneity in tumor cells plays a minor role in resistance mechanisms that may prevent the desired qualitative reprogramming of tumor tissues (Harrer et al., 2023b; Heudobler et al., 2024a) (Figure 1; Tables 1 and 4).

A critical obstacle for editing therapy could be a significant genomic distance between tumor subclones, which is associated with crucial differences in the activity of cancer traits due to the specialization of a tumor cell clone. This experimental finding cannot be excluded as a potential resistance mechanism relevant for clinical trials (Sibai et al., 2022; Harrer et al., 2023b). However, genomic distance between tumor subclones contributing to NOA circuitries that can no longer be targeted by a set of receptor agonists can be excluded as a common phenomenon in r/r HL and mLCH.

Since viability is a prerequisite for tumor growth, the transcriptomic landscape of each tumor should provide targetable transcriptional patterns accessible via receptor-induced nuclear/cytokine receptor NOAs.

Following planned curative systemic therapy, the spectrum of potential toxicities that can significantly impact a patient’s quality of life and long-term health status can be enormous.

Advances in cancer therapies that take advantage of systems-based pharmacological approaches, such as tumor tissue editing techniques, can systematically minimize therapy-related toxicity combined with high specificity in targeting addicted tumor system circuitries (Harrer et al., 2023b; Harrer et al., 2023a) (Table 4).

Systems pharmacology approaches targeting tumor tissue addiction have “indirectly” led to long-term disease control or even CR and cCR via the “loop,” reprogramming of cancer hallmarks, deregulation of stress responses, and ultimately destabilization of the tumor tissue addiction context.

Therefore, editing approaches must not primarily address the question of who is eligible for therapy based on age or comorbidity. Toxicity can be mitigated simply by planned dose reductions that do not compromise response due to the biomodulatory activity of the editing drugs (Harrer et al., 2023b; Harrer et al., 2023a). The minimum activity of each drug in the editing schedules is not known in accordance with the scheduled dose reductions (Harrer et al., 2023b; Harrer et al., 2023a).

Normal tissues attenuate the induced transcriptional regulatory activity profile of nuclear/cytokine receptor agonists to clinically undetectable levels, as tumor-associated addictions are absent in normal tissues.

Scheduled dose reductions keep the toxicities of low dose metronomic chemotherapy low. Treosulfan, trofosfamide or capecitabine have shown very low emetogenic activity (Harrer et al., 2023b).

The modest toxicity patterns observed are known from the toxicity profiles of the individual drugs. The adverse event (AE) and serious adverse event (SAE) data monitored in the phase I/II studies do not indicate any novel toxicities associated with the drug combinations used. Tumor tissue editing approaches are associated with modest off-target effects (Harrer et al., 2023b; Harrer et al., 2023a).

Ubiquitously available receptor-induced transcription factors maintain NOA circuitries, as shown for those involved in tumor-associated inflammation. The inflammation-specific serum biomarker CRP enables CRP-guided precision medicine. Tumor response paralleled CRP response in RCCC, mLCH, HL and melanoma (Reichle et al., 2007a; Ugocsai et al., 2016; Harrer et al., 2022; Reichle et al., 2007b).

Addicted NOA circuitries are key targets that provide specific therapeutic access and are not available in normal tissues with organ-defined cell identity (Tables 3 and 5).

Tumor tissue editing approaches address the overarching goal of modern hematology and oncology to reduce off-target effects while improving treatment outcomes, here even with cCR in quite different histological r/r tumor stages (Tables 3 and 5). Tumor tissue editing approaches target transcriptionally accessible NOAs with analogs of natural receptor ligands at low doses compared to previously used high doses, e.g., of cytokines in RCCC (Atzpodien et al., 2006; Lüke et al., 2021; Harrer et al., 2023b).

Tumor tissue editing approaches represent a new therapeutic technology that enriches personalized medicine by altering tumor tissue addictions to three NOA levels integrated into cancer tissue addictions (Figure 3). Moreover, tumor tissue editing therapies are applicable on an outpatient basis, independent of comorbidities and sequence of pretreatments (Harrer et al., 2025). The cost of drugs used for editing is modest compared to available standard salvage therapies in metastatic r/r neoplasms.