Review

Targeting cellular signaling pathways in cancer by natural compounds

Manal A Tashkandi 1, Mohammed Y Refai 1, and Lina A Baz 1*

1 Department of Biochemistry, College of Science, University of Jeddah, Jeddah-21589 Saudi Arabia.

* Correspondence: hmbaeissa@uj.edu.sa (H.M.B.)

Citation: Tashkandi, M.A., Refai, M.Y., and Baz, L.A. Targeting cellular signaling pathways in cancer by natural compounds. Glob. Jour. Bas. Sci. 2025, 1(7). 1-11.

Received: April 01, 2025

Revised: May 01, 2025

Accepted: May 02, 2025

Published: May 02, 2025

doi: 10.63454/jbs20000031

ISSN: 3049-3315

Volume 1; Issue 7

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Abstract: Computational approaches have become integral to modern anti-cancer research, driven by advances in high-throughput technologies, data availability, and algorithmic innovation. This review provides a comprehensive overview of emerging trends in computational methods that support cancer drug discovery, target identification, biomarker discovery, and treatment optimization. We examine the evolution from traditional bioinformatics and molecular modeling techniques to contemporary data-driven frameworks that integrate genomics, transcriptomics, proteomics, epigenomics, and metabolomics data. Particular emphasis is placed on the growing role of machine learning and deep learning in cancer research, including applications in drug–target interaction prediction, virtual screening, de novo drug design, patient stratification, and outcome prediction. Network-based and systems biology approaches are discussed as powerful tools for modeling cancer complexity, elucidating dysregulated signaling pathways, and identifying multi-target therapeutic strategies. The review also highlights the increasing use of computational methods for immuno-oncology, such as neoantigen prediction, immune profiling, and modeling tumor–immune interactions. In addition, we address the integration of real-world data, electronic health records, and imaging data with molecular datasets to enable precision oncology and personalized treatment strategies. Key challenges, including data heterogeneity, model interpretability, reproducibility, and clinical translation, are critically analyzed. Finally, we outline future directions, emphasizing the need for explainable artificial intelligence, standardized benchmarks, and closer collaboration between computational scientists, biologists, and clinicians to accelerate the development of effective anti-cancer therapies.

Keywords: Cancer signaling pathways; Natural compounds; Phytochemicals; Targeted cancer therapy; Signal transduction; Drug resistance

1. Introduction

Cancer remains one of the leading causes of morbidity and mortality worldwide, accounting for millions of new cases and deaths each year. Despite significant progress in early diagnosis, surgical interventions, radiotherapy, and the development of molecularly targeted therapies, cancer continues to pose a major therapeutic challenge. A fundamental hallmark of cancer is the dysregulation of intracellular signaling pathways that normally regulate cellular processes such as proliferation, differentiation, metabolism, survival, and programmed cell death. Aberrant activation or suppression of these signaling networks enables malignant cells to acquire sustained growth advantages, resist apoptosis, evade immune surveillance, and develop metastatic potential [1-7].

Cellular signaling pathways operate through highly coordinated networks involving receptors, kinases, transcription factors, and regulatory proteins that transmit extracellular and intracellular cues to orchestrate cell fate decisions. In cancer, these pathways are frequently disrupted by genetic mutations, chromosomal rearrangements, epigenetic alterations, and aberrant interactions with the tumor microenvironment. Key oncogenic signaling cascades, including the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK), Janus kinase/signal transducer and activator of transcription (JAK/STAT), Wnt/β-catenin, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Hedgehog, and Notch pathways, have been extensively implicated in tumor initiation, progression, and therapeutic resistance [5-11]. The complexity and extensive crosstalk among these pathways contribute to tumor heterogeneity and limit the long-term efficacy of single-target therapies.

Although targeted anticancer drugs have improved clinical outcomes in several malignancies, their benefits are often compromised by drug resistance, off-target toxicity, and high treatment costs. These limitations have prompted increasing interest in alternative and complementary therapeutic strategies that can modulate multiple signaling pathways with reduced toxicity. In this context, natural compounds derived from plants, dietary sources, marine organisms, and microorganisms have emerged as promising candidates for cancer prevention and therapy[12-19]. Phytochemicals such as curcumin, resveratrol, quercetin, epigallocatechin gallate, genistein, and berberine have demonstrated potent anticancer activities across a wide range of tumor models by targeting key signaling pathways involved in cancer cell survival and proliferation (Figure 1).

Natural compounds possess several advantages over conventional chemotherapeutic agents, including structural diversity, multitargeting capability, relatively low toxicity, and long-standing use in traditional medicine systems. Importantly, many natural products can simultaneously modulate multiple oncogenic  pathways, inhibit inflammation and oxidative stress, regulate epigenetic mechanisms, and sensitize cancer cells to standard therapies. Moreover, growing evidence suggests that natural compounds can influence the tumor microenvironment and cancer stem cell populations, thereby addressing critical drivers of tumor recurrence and metastasis.

This review aims to provide a comprehensive and integrative overview of the role of natural compounds in targeting dysregulated cellular signaling pathways in cancer. We summarize the major oncogenic signaling networks involved in tumorigenesis and discuss how diverse natural compounds modulate these pathways to exert anticancer effects. In addition, we highlight recent advances in combination strategies, challenges in clinical translation, and future perspectives for harnessing natural compounds as effective signaling-based interventions in cancer therapy. 

2. Overview of Cellular Signaling Pathways in Cancer

Cancer development and progression are driven by profound alterations in cellular signaling pathways that normally regulate cell growth, differentiation, metabolism, and survival. These signaling networks consist of complex, highly interconnected cascades involving cell surface receptors, intracellular kinases, transcription factors, and regulatory proteins. In malignant cells, persistent dysregulation of these pathways enables the acquisition of hallmark cancer traits, including sustained proliferative signaling, resistance to cell death, genomic instability, immune evasion, angiogenesis, and metastatic dissemination. Understanding the organization and regulation of oncogenic signaling networks is therefore fundamental to deciphering cancer biology and developing effective therapeutic strategies [15-25].

2.1 Role of Signaling Networks in Tumor Initiation and Progression

Cellular signaling pathways play a central role in both the initiation and progression of cancer by controlling key cellular decisions such as proliferation, differentiation, senescence, and apoptosis (Figure 2). In normal tissues, these pathways are tightly regulated  and activated only in response to specific extracellular stimuli, including growth factors, cytokines, and cell–cell interactions. In cancer, however, genetic mutations and epigenetic alterations lead to constitutive activation or inappropriate suppression of these pathways, allowing cells to bypass normal regulatory checkpoints.

Oncogenic signaling pathways such as PI3K/AKT/mTOR and MAPK/ERK promote sustained cell growth and survival, while aberrant activation of JAK/STAT signaling enhances inflammatory responses and immune evasion. Developmental pathways, including Wnt/β-catenin, Hedgehog, and Notch, which are essential for embryogenesis and tissue homeostasis, are frequently reactivated in tumors and contribute to cancer stem cell maintenance, differentiation blockade, and tumor heterogeneity. Collectively, these dysregulated signaling networks drive tumor initiation by enabling clonal expansion of transformed cells and support tumor progression through enhanced invasion, angiogenesis, and metastatic potential. 

2.2 Crosstalk and Redundancy Among Signaling Pathways

A defining feature of cancer-associated signaling networks is the extensive crosstalk and functional redundancy among pathways. Rather than operating as linear, isolated cascades, signaling pathways form highly interconnected networks that can compensate for one another when individual nodes are inhibited. For example, inhibition of the PI3K/AKT/mTOR pathway may result in compensatory activation of MAPK/ERK signaling, thereby sustaining tumor cell survival and proliferation. Similarly, crosstalk between NF-κB, JAK/STAT, and MAPK pathways integrates inflammatory and oncogenic signals to promote tumor progression.

This signaling redundancy poses a major challenge for targeted cancer therapies, as single-pathway inhibition often leads to adaptive resistance and disease relapse. Cancer cells exploit pathway plasticity to rewire signaling networks in response to therapeutic pressure, underscoring the need for multitarget or combination treatment strategies. Natural compounds, which often modulate multiple signaling pathways simultaneously, may offer a distinct advantage in overcoming pathway redundancy and resistance mechanisms.

2.3 Genetic, Epigenetic, and Microenvironmental Regulation

The dysregulation of signaling pathways in cancer is driven by a combination of genetic, epigenetic, and microenvironmental factors. Genetic alterations such as point mutations, gene amplifications, deletions, and chromosomal rearrangements frequently affect key signaling components, including receptor tyrosine kinases, intracellular kinases, and transcription factors. Mutations in genes encoding signaling regulators can result in constitutive pathway activation or loss of tumor suppressor function. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, further modulate signaling pathway activity without altering the underlying DNA sequence. These epigenetic changes can silence tumor suppressor genes or enhance oncogenic signaling, contributing to tumor heterogeneity and therapeutic resistance. Additionally, the tumor microenvironment—including stromal cells, immune cells, extracellular matrix components, cytokines, and hypoxic conditions—plays a critical role in shaping cancer signaling networks. Microenvironment-derived signals can activate survival pathways, promote angiogenesis, and facilitate immune escape, thereby reinforcing malignant behavior [26-32].

Together, the integration of genetic, epigenetic, and microenvironmental influences creates a dynamic and adaptive signaling landscape that drives cancer initiation, progression, and resistance to therapy. Targeting these interconnected regulatory layers represents a promising strategy for the development of more effective and durable anticancer treatments.

3. Natural Compounds as Modulators of Cancer Signaling

Natural compounds have gained increasing attention as promising modulators of dysregulated cellular signaling pathways in cancer. Owing to their remarkable chemical diversity and broad biological activities, natural products have historically served as a rich source of therapeutic agents, including several anticancer drugs currently used in clinical practice. Recent advances in molecular oncology have further highlighted the ability of natural compounds to target key oncogenic signaling pathways involved in tumor initiation, progression, and resistance to therapy [26-27].

3.1 Definition and Classification of Natural Compounds

Natural compounds are bioactive chemical substances produced by living organisms, including plants, microorganisms, and marine species. These compounds often serve ecological functions such as defense, communication, or survival and possess unique structural features that enable interaction with diverse molecular targets. In cancer research, natural compounds are commonly classified based on their chemical structure and biosynthetic origin. Major classes include polyphenols, flavonoids, alkaloids, terpenoids, glycosides, quinones, and saponins. Each class encompasses numerous compounds with distinct pharmacological properties and mechanisms of action.

From a functional perspective, natural compounds can also be categorized according to their effects on cellular signaling, such as kinase inhibitors, transcription factor modulators, epigenetic regulators, antioxidants, and apoptosis inducers. Importantly, many natural products exert pleiotropic effects by simultaneously modulating multiple signaling pathways, a feature that distinguishes them from highly selective synthetic drugs.

3.2 Sources of Natural Compounds

Natural compounds with anticancer potential are derived from a wide range of biological sources. Plant-derived compounds represent the most extensively studied group and include well-known phytochemicals such as curcumin, resveratrol, quercetin, genistein, epigallocatechin gallate, and berberine. These compounds are abundant in medicinal plants, fruits, vegetables, and traditional herbal formulations. Marine organisms, including sponges, algae, tunicates, and marine microorganisms, have emerged as valuable sources of structurally novel bioactive compounds with potent anticancer activity. Several marine-derived agents exhibit unique mechanisms of action and have advanced into clinical development. Microbial sources, particularly bacteria and fungi, produce a diverse array of secondary metabolites with signaling-modulatory properties, many of which form the basis of modern chemotherapeutic agents. In addition, dietary agents, such as vitamins, carotenoids, and omega-3 fatty acids, contribute to cancer prevention and therapy by modulating oxidative stress, inflammation, and cell signaling pathways [26-27].

3.3 Advantages Over Synthetic Drugs

Natural compounds offer several advantages over conventional synthetic anticancer drugs. Their ability to target multiple signaling pathways simultaneously allows for broader therapeutic effects and may reduce the likelihood of resistance arising from pathway redundancy and compensatory signaling. Many natural compounds exhibit relatively low systemic toxicity and have a long history of human consumption, supporting their potential safety. Furthermore, natural products often enhance the efficacy of standard chemotherapeutic agents, allowing for dose reduction and decreased adverse effects when used in combination therapies.

3.4 Challenges: Bioavailability, Toxicity, and Standardization

Despite their therapeutic promise, the clinical translation of natural compounds faces several challenges. Poor bioavailability due to low solubility, limited absorption, rapid metabolism, and fast clearance remains a major limitation for many phytochemicals. Additionally, although generally considered safe, some natural compounds can exhibit toxicity at high doses or interact adversely with conventional drugs. Another critical challenge is the lack of standardization in natural product preparations, as variations in source, extraction methods, and formulation can lead to inconsistent bioactivity and reproducibility.

Addressing these challenges through advanced drug delivery systems, structural optimization, rigorous toxicological evaluation, and standardized manufacturing practices will be essential to fully harness the potential of natural compounds as modulators of cancer signaling pathways.

4. Targeting Major Oncogenic Signaling Pathways by Natural Compounds

Aberrant activation of oncogenic signaling pathways is a central driver of cancer initiation, progression, and therapeutic resistance. Natural compounds have emerged as effective modulators of these pathways due to their ability to interact with multiple molecular targets simultaneously. This multitargeting property is particularly advantageous in cancer, where signaling redundancy and pathway crosstalk often undermine the efficacy of highly selective synthetic inhibitors [32-42]. Below, we summarize the major oncogenic signaling pathways implicated in cancer and discuss representative natural compounds that modulate their activity (Figure 3).

4.1 PI3K/AKT/mTOR Pathway

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is a master regulator of cell proliferation, survival, metabolism, and angiogenesis. Constitutive activation of this pathway is one of the most frequently observed signaling abnormalities in human cancers and is commonly driven by mutations in PI3K, loss of PTEN tumor suppressor function, or upstream receptor tyrosine kinase activation. Hyperactivation of PI3K/AKT/mTOR signaling promotes uncontrolled cell growth, inhibits apoptosis, enhances glycolytic metabolism, and contributes to resistance against chemotherapy and radiotherapy.

Several natural compounds have been shown to inhibit PI3K/AKT/mTOR signaling at multiple levels. Curcumin, a polyphenol derived from Curcuma longa, suppresses PI3K and AKT phosphorylation and inhibits mTOR activity, leading to reduced proliferation and increased apoptosis in various cancer models. Resveratrol, a stilbene found in grapes and berries, downregulates AKT signaling and disrupts mTOR-mediated metabolic pathways. Quercetin, a flavonoid abundant in fruits and vegetables, inhibits PI3K activity and sensitizes cancer cells to apoptosis, highlighting the therapeutic potential of natural PI3K/AKT/mTOR inhibitors [40-50].

4.2 MAPK/ERK Pathway

The mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) pathway plays a crucial role in regulating  cell growth, differentiation, and survival. Activation of this pathway is initiated by extracellular growth factors and mediated through RAS–RAF–MEK–ERK signaling cascades. Persistent MAPK/ERK activation, often caused by mutations in RAS or BRAF, drives excessive proliferation and contributes to malignant transformation.

Multiple phytochemicals have been reported to modulate MAPK signaling. Epigallocatechin gallate (EGCG) from green tea inhibits ERK phosphorylation and suppresses tumor cell proliferation. Curcumin and resveratrol also interfere with MAPK signaling by targeting upstream kinases and transcriptional regulators, thereby inhibiting tumor growth and inducing cell cycle arrest. These findings support the use of natural compounds as modulators of MAPK-driven cancers.

 

4.3 JAK/STAT Pathway

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a critical mediator of cytokine signaling and plays an essential role in inflammation, immune regulation, and cancer progression. Aberrant activation of STAT proteins, particularly STAT3 and STAT5, promotes tumor cell survival, immune evasion, angiogenesis, and metastasis.

Natural compounds such as curcumin, resveratrol, berberine, and withaferin A have been shown to inhibit STAT activation by suppressing upstream JAK kinases or directly blocking STAT phosphorylation and nuclear translocation. By targeting JAK/STAT signaling, these compounds reduce inflammatory cytokine production and enhance antitumor immune responses [50-53].

4.4 Wnt/β-Catenin Pathway

The Wnt/β-catenin signaling pathway is a key regulator of embryonic development, tissue homeostasis, and stem cell maintenance. In cancer, aberrant activation of Wnt signaling contributes to tumor initiation, progression, and the maintenance of cancer stem cells, which are implicated in metastasis and therapeutic resistance. Several natural compounds modulate Wnt/β-catenin signaling. Sulforaphane, found in cruciferous vegetables, promotes β-catenin degradation and suppresses cancer stem cell self-renewal. Curcumin and genistein inhibit Wnt ligand expression and β-catenin transcriptional activity, thereby reducing tumor growth and invasiveness [8-9,12].

4.5 NF-κB Pathway

Nuclear factor kappa B (NF-κB) is a central regulator of inflammation, immune responses, and cell survival. Chronic NF-κB activation is commonly observed in cancer and promotes tumor progression by inducing inflammatory cytokines, anti-apoptotic proteins, and angiogenic factors. Natural anti-inflammatory agents such as curcumin, resveratrol, parthenolide, and gingerol effectively inhibit NF-κB activation by blocking IκB kinase activity and preventing NF-κB nuclear translocation. Suppression of NF-κB signaling leads to reduced inflammation, enhanced apoptosis, and increased sensitivity to anticancer therapies [10].

4.6 Hedgehog and Notch Pathways

Hedgehog and Notch signaling pathways are essential for embryonic development and tissue regeneration but are frequently reactivated in cancer, where they contribute to tumor growth, stemness, and therapy resistance. Aberrant Hedgehog signaling promotes proliferation and survival, while dysregulated Notch signaling influences cell fate determination and tumor aggressiveness. Natural pathway antagonists have shown promising inhibitory effects. Cyclopamine, a plant-derived alkaloid, inhibits Hedgehog signaling by targeting Smoothened. Curcumin, resveratrol, and genistein have been reported to suppress Notch signaling components, leading to reduced tumor growth and enhanced differentiation [12-13].

Collectively, these findings demonstrate that natural compounds can effectively target multiple oncogenic signaling pathways involved in cancer development and progression. Their multitargeting capacity, combined with relatively low toxicity, highlights their potential as complementary or alternative therapeutic agents in signaling-based cancer treatment strategies.

5. Regulation of Apoptosis and Cell Cycle by Natural Compounds

Evasion of apoptosis and deregulated cell cycle progression are fundamental hallmarks of cancer that enable malignant cells to survive under oncogenic stress and proliferate uncontrollably. Apoptotic signaling pathways and cell cycle checkpoints are tightly regulated in normal cells to maintain tissue homeostasis; however, in cancer, these regulatory mechanisms are frequently disrupted through genetic and epigenetic alterations. Natural compounds have demonstrated significant potential to restore apoptotic signaling and enforce cell cycle arrest by targeting multiple regulatory nodes, thereby suppressing tumor growth and enhancing therapeutic sensitivity.

5.1 Intrinsic and Extrinsic Apoptotic Pathways

Apoptosis is primarily mediated through two major pathways: the intrinsic (mitochondrial) pathway and the extrinsic (death receptor–mediated) pathway. The intrinsic pathway is activated in response to intracellular stress signals such as DNA damage, oxidative stress, and oncogene activation, leading to mitochondrial outer membrane permeabilization and the release of pro-apoptotic factors, including cytochrome c. This process triggers the activation of initiator caspase-9, followed by executioner caspases such as caspase-3 and caspase-7. The extrinsic pathway is initiated by the binding of death ligands, such as Fas ligand or tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), to their corresponding cell surface receptors, resulting in caspase-8 activation [36].

Numerous natural compounds have been shown to activate both apoptotic pathways in cancer cells. Curcumin, resveratrol, and berberine induce mitochondrial dysfunction and caspase activation, while also enhancing death receptor expression and sensitizing tumor cells to extrinsic apoptotic signals. By simultaneously engaging both apoptotic pathways, these compounds effectively overcome apoptosis resistance commonly observed in cancer.

5.2 Modulation of the BCL-2 Family of Proteins

The BCL-2 family of proteins serves as a central regulatory hub of the intrinsic apoptotic pathway and comprises both pro-apoptotic (e.g., BAX, BAK, BIM) and anti-apoptotic (e.g., BCL-2, BCL-XL, MCL-1) members. In many cancers, overexpression of anti-apoptotic BCL-2 family proteins promotes cell survival and contributes to resistance against chemotherapy and targeted therapies. Natural compounds have been shown to modulate the balance between pro- and anti-apoptotic BCL-2 family proteins. Quercetin, EGCG, and genistein downregulate BCL-2 and BCL-XL expression while upregulating BAX and BAK, thereby promoting mitochondrial membrane permeabilization and apoptosis. Additionally, resveratrol and curcumin have been reported to inhibit MCL-1 expression, further sensitizing cancer cells to apoptotic stimuli. These findings highlight the potential of natural compounds as functional BCL-2 pathway modulators [37].

5.3 Cell Cycle Arrest Mechanisms

Uncontrolled cell cycle progression is a defining feature of cancer and results from dysregulation of cyclins, cyclin-dependent kinases (CDKs), and their inhibitors. Natural compounds exert anticancer effects by inducing cell cycle arrest at specific checkpoints, particularly the G0/G1, S, and G2/M phases. This arrest is often mediated through the downregulation of cyclins (e.g., cyclin D1, cyclin E) and CDKs, along with the upregulation of CDK inhibitors such as p21^Cip1^ and p27^Kip1^.

Curcumin and resveratrol induce G1/S arrest by suppressing cyclin D1 and CDK4/6 activity, whereas quercetin and genistein have been shown to trigger G2/M arrest through inhibition of cyclin B1 and CDK1. In addition, several natural compounds activate the p53 tumor suppressor pathway, leading to DNA damage–induced cell cycle arrest and apoptosis. By halting cell cycle progression, these compounds limit tumor cell proliferation and enhance susceptibility to apoptotic signaling. Collectively, natural compounds effectively restore apoptotic signaling and enforce cell cycle checkpoints in cancer cells by modulating intrinsic and extrinsic apoptotic pathways, regulating BCL-2 family proteins, and targeting key cell cycle regulators. These multitargeted effects underscore the therapeutic potential of natural compounds as critical modulators of cancer cell survival and proliferation [38].

6. Epigenetic Modulation of Cancer Signaling

Epigenetic dysregulation plays a critical role in cancer initiation, progression, and therapeutic resistance by altering gene expression without changes in the underlying DNA sequence. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, interact closely with oncogenic signaling pathways to shape the malignant phenotype [22,23,26,28,43]. Natural compounds have emerged as promising epigenetic modulators capable of restoring normal gene expression patterns and sensitizing cancer cells to therapy (Figure 4).   

6.1 DNA Methylation and Histone Modification

Aberrant DNA methylation, particularly hypermethylation of tumor suppressor gene promoters and global hypomethylation leading to genomic instability, is a hallmark of cancer. Similarly, dysregulated histone modifications, such as altered acetylation and methylation, influence chromatin accessibility and transcriptional activity of key signaling genes. These epigenetic alterations frequently converge on oncogenic pathways including PI3K/AKT, Wnt/β-catenin, and NF-κB, thereby reinforcing malignant signaling.

Natural compounds such as curcumin, EGCG, and resveratrol have been shown to inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), leading to reactivation of silenced tumor suppressor genes and suppression of oncogenic signaling. By modifying chromatin structure and transcriptional regulation, these compounds exert broad anticancer effects.

6.2 Natural Epigenetic Regulators

Several phytochemicals function as natural epigenetic regulators. Sulforaphane acts as an HDAC inhibitor and modulates histone acetylation, while genistein influences DNA methylation patterns and histone modifications associated with cell cycle and apoptotic genes. Berberine and resveratrol also regulate microRNAs that target key signaling molecules, further amplifying their epigenetic impact. These natural epigenetic modulators provide a multifaceted approach to disrupting cancer signaling networks.

6.3 Reversal of Drug Resistance

Epigenetic alterations are a major contributor to drug resistance in cancer. Natural compounds can reverse resistance by re-sensitizing cancer cells to chemotherapy and targeted therapies through epigenetic reprogramming. By restoring apoptotic signaling, downregulating drug efflux transporters, and inhibiting survival pathways, natural epigenetic regulators enhance therapeutic efficacy and reduce relapse.

7. Targeting the Tumor Microenvironment and Cancer Stem Cells

The tumor microenvironment (TME) plays a pivotal role in cancer progression and therapy resistance by providing biochemical and physical support to malignant cells. It consists of stromal cells, immune cells, extracellular matrix components, cytokines, and hypoxic niches that collectively modulate oncogenic signaling pathways [29-30].

Cancer-associated fibroblasts, immune cells, and endothelial cells secrete growth factors and cytokines that activate signaling pathways such as JAK/STAT, NF-κB, and PI3K/AKT in tumor cells. Hypoxia within the TME stabilizes hypoxia-inducible factors (HIFs), promoting angiogenesis, metabolic reprogramming, and metastatic potential. Natural compounds like resveratrol, curcumin, and quercetin suppress cytokine signaling and inhibit HIF-1α activity, thereby disrupting TME-driven tumor support.

Angiogenesis and metastasis are critical processes regulated by the TME. Natural compounds such as EGCG, curcumin, and berberine inhibit vascular endothelial growth factor (VEGF) signaling and matrix metalloproteinase activity, reducing tumor vascularization and invasion. These effects limit nutrient supply to tumors and impair metastatic dissemination.

Cancer stem cells (CSCs) contribute to tumor recurrence, metastasis, and drug resistance through activation of signaling pathways including Wnt/β-catenin, Notch, and Hedgehog. Natural compounds such as sulforaphane, curcumin, and genistein have been shown to target CSC populations by suppressing self-renewal signaling and inducing differentiation, thereby enhancing long-term therapeutic outcomes.

8. Natural Compounds in Combination Therapy

Combination therapy represents a promising strategy to overcome the limitations of monotherapies in cancer treatment. Natural compounds are increasingly explored as adjuvants to conventional chemotherapy and targeted agents due to their multitargeting capabilities and favorable safety profiles.

Natural compounds can enhance the efficacy of chemotherapeutic and targeted agents by modulating survival and resistance pathways. For example, curcumin and resveratrol potentiate the effects of kinase inhibitors and DNA-damaging agents by suppressing compensatory signaling pathways and promoting apoptosis. Such synergistic interactions improve therapeutic response and delay resistance development. Therapeutic resistance often arises from pathway redundancy, epigenetic reprogramming, and TME-mediated protection. Natural compounds counteract these mechanisms by targeting multiple signaling nodes, reversing epigenetic changes, and sensitizing cancer cells to treatment. Their ability to inhibit drug efflux pumps and survival signaling further enhances treatment efficacy. Incorporation of natural compounds into combination regimens may allow for reduced doses of conventional anticancer drugs, thereby minimizing systemic toxicity and improving patient tolerance. This dose-sparing effect is particularly valuable in long-term treatment settings and in vulnerable patient populations. Together, these findings highlight the critical role of natural compounds in modulating epigenetic regulation, the tumor microenvironment, cancer stem cell signaling, and therapeutic response. Their integration into modern cancer treatment strategies offers a promising avenue for enhancing efficacy, overcoming resistance, and reducing treatment-related toxicity [9,15,34,35,42,44,48].

9. Clinical Evidence and Translational Potential

Despite extensive preclinical evidence supporting the anticancer activity of natural compounds, successful clinical translation remains a significant challenge. Bridging the gap between laboratory findings and patient outcomes requires careful evaluation of pharmacokinetics, dosing, formulation, and patient selection.

9.1 Preclinical vs. Clinical Findings

Preclinical studies using cell lines and animal models have consistently demonstrated that natural compounds can modulate key oncogenic signaling pathways, including PI3K/AKT/mTOR, MAPK, NF-κB, Wnt/β-catenin, and JAK/STAT. These studies highlight potent antiproliferative, pro-apoptotic, anti-inflammatory, and anti-metastatic effects. However, clinical trials often report modest or variable outcomes, primarily due to differences in bioavailability, metabolic stability, and achievable plasma concentrations in humans.

Additionally, tumor heterogeneity and differences between experimental models and human cancers limit direct extrapolation. While in vitro studies frequently use supra-physiological concentrations, such levels are difficult to attain safely in clinical settings. These discrepancies underscore the importance of improved translational models and optimized formulations.

9.2 Ongoing Clinical Trials

Several natural compounds have progressed into early- and late-phase clinical trials, either as monotherapies or as adjuncts to standard treatments. Curcumin, resveratrol, EGCG, sulforaphane, and berberine are among the most extensively investigated compounds. Clinical studies have evaluated their effects in colorectal, breast, prostate, pancreatic, and hematological malignancies. Most trials focus on safety, tolerability, pharmacokinetics, and biomarker modulation rather than direct survival outcomes. Emerging evidence suggests that these compounds can modulate inflammatory markers, oxidative stress, and signaling pathway activity in patients, supporting their biological activity in vivo. Ongoing trials incorporating advanced delivery systems and combination strategies are expected to provide more definitive insights into clinical efficacy.

9.3 Limitations in Clinical Translation

Key limitations hindering clinical translation include poor oral bioavailability, rapid metabolism, inter-individual variability, lack of standardized formulations, and limited regulatory frameworks. Inconsistent trial design, small sample sizes, and absence of validated predictive biomarkers further complicate interpretation of clinical outcomes. Addressing these challenges is critical for the successful integration of natural compounds into evidence-based oncology practice.

10. Challenges and Future Perspectives

The successful clinical application of natural compounds in targeting cancer signaling pathways depends on overcoming several biological, technological, and methodological challenges. Advances in formulation science, precision medicine, and systems biology offer promising solutions.

10.1 Bioavailability and Formulation Strategies

Many natural compounds suffer from low solubility, poor absorption, and rapid clearance, limiting their therapeutic efficacy. Strategies such as structural modification, use of bioenhancers, prodrug development, and formulation with lipids or polymers have shown promise in improving pharmacokinetic profiles. Standardization of extracts and rigorous quality control are also essential to ensure reproducibility and regulatory compliance.

10.2 Nanotechnology-Based Delivery

Nanotechnology-based delivery systems represent a transformative approach to enhance the clinical utility of natural compounds. Nanoparticles, liposomes, micelles, and polymeric carriers improve solubility, stability, tumor targeting, and controlled release. These platforms can also facilitate co-delivery of natural compounds with chemotherapeutic agents, enabling synergistic effects and reduced toxicity. Nanomedicine thus holds significant potential for overcoming pharmacological limitations and improving therapeutic outcomes.

10.3 Precision Medicine Approaches

The heterogeneity of cancer necessitates personalized therapeutic strategies. Integrating natural compounds into precision medicine frameworks requires identification of patient subgroups most likely to benefit, based on molecular signatures and pathway dependencies. Biomarker-driven clinical trials and omics-based profiling can guide rational selection of natural compounds and combinations, maximizing efficacy while minimizing unnecessary exposure.

10.4 Future Research Directions

Future research should focus on well-designed, large-scale clinical trials with standardized formulations and robust endpoints. Systems biology and network pharmacology approaches can help elucidate the multitarget effects of natural compounds and identify optimal combination strategies. Additionally, exploration of natural compound libraries and structure–activity relationships may yield novel derivatives with improved potency and pharmacological properties.

11. Conclusion

This review highlights the central role of dysregulated cellular signaling pathways in cancer and the potential of natural compounds to modulate these networks at multiple levels. Natural compounds target oncogenic signaling, induce apoptosis and cell cycle arrest, regulate epigenetic mechanisms, reshape the tumor microenvironment, and inhibit cancer stem cell signaling.

By acting on multiple interconnected pathways, natural compounds offer a systems-level approach to cancer therapy that complements conventional single-target strategies. Their ability to enhance therapeutic efficacy, overcome resistance, and reduce toxicity underscores their value as adjuncts in modern oncology. Although significant challenges remain, advances in formulation science, nanotechnology, and precision medicine are rapidly improving the translational potential of natural compounds. With continued interdisciplinary research and well-structured clinical validation, natural compounds hold substantial promise as integral components of cancer signaling–based therapeutic strategies.

Author Contributions: Conceptualisation, M.A.T., M.Y.R., and L.A.B.; software, L.A.B.; investigation, M.A.T., M.Y.R., and L.A.B.;  writing—original draft preparation, M.A.T., M.Y.R., and L.A.B.; writing—review and editing, M.A.T., M.Y.R., and L.A.B.; visualisation, M.A.T., M.Y.R., and L.A.B.; supervision, M.A.T. and L.A.B.; project administration, L.A.b. The author has read and agreed to the published version of the manuscript.

Funding: Not applicable.

Acknowledgments: We are grateful to the Department of Biochemistry, College of Science, University of Jeddah, Jeddah-21589 Saudi Arabia for providing us all the facilities to carry out the entire work.

Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: All the related data are supplied in this work or have been referenced properly.

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