Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

Background Tumors often progress to a more aggressive phenotype to resist drugs. Multiple dysregulated pathways are behind this tumor behavior which is known as cancer chemoresistance. Thus, there is an emerging need to discover pivotal signaling pathways involved in the resistance to chemotherapeutic agents and cancer immunotherapy. Reports indicate the critical role of the toll-like receptor (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor pyrin domain-containing (NLRP) pathway in cancer initiation, progression, and development. Therefore, targeting TLR/NF-κB/NLRP signaling is a promising strategy to augment cancer chemotherapy and immunotherapy and to combat chemoresistance. Considering the potential of phytochemicals in the regulation of multiple dysregulated pathways during cancer initiation, promotion, and progression, such compounds could be suitable candidates against cancer chemoresistance. Objectives This is the first comprehensive and systematic review regarding the role of phytochemicals in the mitigation of chemoresistance by regulating the TLR/NF-κB/NLRP signaling pathway in chemotherapy and immunotherapy. Methods A comprehensive and systematic review was designed based on Web of Science, PubMed, Scopus, and Cochrane electronic databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to include papers on TLR/NF-κB/NLRP and chemotherapy/immunotherapy/chemoresistance by phytochemicals. Results Phytochemicals are promising multi-targeting candidates against the TLR/NF-κB/NLRP signaling pathway and interconnected mediators. Employing phenolic compounds, alkaloids, terpenoids, and sulfur compounds could be a promising strategy for managing cancer chemoresistance through the modulation of the TLR/NF-κB/NLRP signaling pathway. Novel delivery systems of phytochemicals in cancer chemotherapy/immunotherapy are also highlighted. Conclusion Targeting TLR/NF-κB/NLRP signaling with bioactive phytocompounds reverses chemoresistance and improves the outcome for chemotherapy and immunotherapy in both preclinical and clinical stages.


INTRODUCTION
Chemoresistance occurs when tumors mutate in response to cancer chemotherapy, yielding a more aggressive phenotype that results in chemotherapy failure (1). This has been a major obstacle in cancer chemotherapy and immunotherapy. Despite various attempts to overcome drug resistance and restore the sensitivity of chemotherapeutic drugs, the results thus far have been unsatisfactory (2). Several pathophysiological mechanisms and multiple dysregulated pathways are responsible for chemotherapy and immunotherapy resistance. Thus, revealing the critical dysregulated pathways in cancer chemoresistance would improve clinical outcomes and prevent/manage the development of chemoresistance, therefore limiting the progression and invasion of cancer (3). Amongst the dysregulated mediators, toll-like receptor (TLR) (4), nuclear factor-kB (NF-kB), and Nod-like receptor pyrin domain-containing (NLRP) (5), as well as the associated TLR/NF-kB/NLRP pathway, have been shown to contribute to cancer chemoresistance. In recent years, researchers have been seeking novel alternative agents with multiple targets, higher efficacy, and less side effects that can combat cancer chemoresistance.
Plant secondary metabolites are multi-targeting anticancer agents that target the cancer-associated pathways, including cellular senescence (6), Hippo signaling (7), Wnt/b-catenin (8), Janus kinase (JAK)/signal transducer and activator of transcription (STAT) (9), phosphoinositide 3-kinases (PI3K)/ Akt/mammalian target of rapamycin (mTOR) (10), hypoxiainducible factor-1a (HIF-1a) (11), and activator protein 1 (AP-1) (12). Phenolic compounds, alkaloids, terpenes/terpenoids, and sulfur-containing compounds demonstrated anticancer potential by modulating tumorigenic signaling pathways (6,13). Emerging evidence has shown the influence of chemoresistance on cancer therapy (5,14,15). Although phytochemicals have exhibited critical regulatory roles in the modulation of TLR, NF-kB, and NLRP in combating cancer (16)(17)(18), there is no review report on the potential of phytochemicals in targeting TLR/NF-kB/NLRP pathway and pivotally interconnected pathways during chemoresistance. Thus, there is an imperative need to discover the precise dysregulated pathways involved in chemoresistance as well as to develop new strategies and alternative therapies to combat cancer chemoresistance. This is the first systematic and comprehensive review regarding crucial chemoresistance mechanisms and the therapeutic potential of plant secondary metabolites in combating cancer chemoresistance by targeting the TLR/NF-kB pathway and interconnected mediators.
The need to develop novel phytocompound delivery systems to fight cancer chemoresistance is also highlighted.

RESISTANCE MECHANISMS IN CANCER CHEMOTHERAPY
Chemoresistance is one of the critical obstacles that affects the efficacy of anticancer drugs. Several factors contribute to the development of cancer chemoresistance. The most common cause of resistance to anticancer agents is the overexpression of energy-dependent transporters that export anticancer agents from the cancer cells (1). Consequently, decreased drug accumulation is another manner of chemotherapeutic resistance, which prevents drug-induced DNA damage and cancer cell apoptosis. Reduced sensitivity to drug-associated apoptosis plays a vital role in the resistance to anticancer drugs (19). Chemotherapy failure can be contributed in part to specific genetic and epigenetic alterations in addition to host factors. Cancer cells have a variety of genetic alterations depending on the tissue and patterns of oncogene activation and tumor suppressor gene inactivation. The use of powerful anticancer agents on cancer cells with these genetic factors leads to the development of drug-resistance mechanisms and the rapid achievement of chemoresistance in various cancer types. Host elements, such as rapid metabolism, poor absorption, and drug excretion, cause low serum levels of the drugs and thus a disposition towards chemoresistance. Host factors also reduce drug delivery to the tumor site, especially in solid bulky tumors with low cell penetration and high molecular weight. Additional mechanisms of cancer cell chemoresistance include receptor loss and mutations in the drug binding site (20).
The administration of various drugs has shown promising effects on chemotherapy with high cure rates by targeting multiple mechanisms of cell entrance. However, cancer cells may develop adaptations to resist these chemotherapeutic drugs, termed multidrug resistance (MDR). MDR strategies include reduced drug accumulation within the cancer cells, decreased uptake, increased efflux, and changes in the membrane lipid properties. These MDR mechanisms limit the apoptosis in cancer cells that are typically induced by anticancer agents, reduce DNA repair mechanisms, and dysregulate the cell cycle and checkpoints in cancer cells. An alternative method to overcome MDR is the use of combination therapy (21). Multidrug resistance proteins (MRPs) decrease the efficacy of anticancer drugs and decrease drug penetration in cancer cells. An additional therapeutic approach involves identifying MDR biomarkers before or during the treatment program (22,23).
Reduced drug uptake and cell surface molecule mutations are other drug resistance mechanisms. Methods of drug entry into cells includes endocytosis and receptor binding followed by internalization of the drug. An example of the later strategy includes immunotoxins. Cancer cells with defective endocytosis are resistant to immunotoxins and toxins (24,25).
Drug efflux from cancer cells is accomplished through various pumps. For example, ATP-binding cassette (ABC) transporters [e.g., P-glycoprotein (P-gp)] play an essential role in drug-related clinical resistance. P-gp levels are increased in several cancers through typical molecular mechanisms and directly correlate with chemotherapy resistance (26). Thus, P-gp expressing cells develop in tumors following in vivo exposure to chemotherapeutic agents. In certain cancer types, elevated P-gp resulted in clinical relapse and decreased P-gp showed therapeutic potential. Accordingly, drugs transported by P-gp have a low chemotherapy response. Therefore, P-gp inhibitors have therapeutic potential in chemotherapy. Despite the high expression of P-gp in solid tumors (e.g., colon and renal cancer), no chemoresistance was shown, implying other methods of drug resistance are at work. Recent research has demonstrated the involvement of the ABC transporter multixenobiotic resistance (MXR) and MRPs in drug resistance. These results express the need to consider treatment with nonspecific inhibitors of ABC transporters or a cocktail of specific inhibitors with the broadest spectrum effect (27).
Another mechanism of chemoresistance is reduced intracellular drug activation and improved drug inactivation by phase I and/or II enzymes in the intestine, liver, and tumor (28). Cytochrome P450s (CYPs) are critical phase I metabolism enzymes that act as an oxidation catalyzer in many anticancer drugs. Genetic mutations in CYPs have shown significant effects on the toxicity and efficacy of anticancer agents that are primarily metabolized by CYPs. Carboxylesterase, deoxycytidine, cytidine deaminase, kinase, and epoxide hydrolase are enzymes involved in the detoxification and/or activation of some anticancer drugs. Mutations in these enzymes may alter their activity and play a role in the chemoresistance process. Cancer cells can become drug-resistant by decreasing drug activation through the reduction or mutation of kinases (29). The aforementioned dysregulated mechanisms that contribute to chemoresistance lead to rapid metabolism/excretion, poor tolerance and downstream oxidative stress, apoptosis/autophagy, and inflammation. Figure 1 summarizes the major factors involved in cancer chemoresistance.
In addition to the above mechanisms, evasion of apoptosis/ autophagy/necrosis is critical to tumor resistance. In any pathological condition, programmed cell death pathways, including apoptosis, and autophagy are the cause of death through intracellular pathways. Such cell death programs may cooperatively determine the fate of malignant neoplasms. Programmed necrosis and apoptosis always contribute to cell death, however, autophagy can play either pro-death or pro-survival roles (30). The mitochondrial (intrinsic) pathway and death receptor (extrinsic) pathway are two methods of apoptosis. Initiation of both pathways ultimately proceeds through caspaserelated cascades. A group of cysteine proteases plays an important role in inflammation and apoptosis by cleaving a variety of nuclear and cytoplasmic mediators. Apoptotic caspases can be either initiator or executioner caspases. These include initiator caspase-2, caspase-8, caspase-9, and caspase-10 and executioner caspase-3, caspase-6, and caspase-7. In regard to the initiator caspases, CD95 (APO-1/Fas) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) are members of the TNF receptor superfamily of death receptors which recruits caspase-8, forming a multimeric complex at the plasma membrane that subsequently activates caspase-3. Caspase-8 causes the release of cytochrome c by increasing the permeability of the outer mitochondrial membrane through cleavage of Bid, a BH3-only protein, and translocation to the mitochondria (31,32). Mitochondrial apoptosis-induced channel (MAC) also increases the release of cytochrome c, which activates caspase-3 through the creation of pro-caspase-9, apoptotic protease activating factor 1 (Apaf-1), and the apoptosome. The apoptosome converts pro-caspase-9 to its active form, caspase-9, which then activates caspase-3 (31). Apaf-1 forms an oligomeric apoptosome which determines the apoptotic pathway upon binding with ATP and cytochrome c. Such apoptotic pathways are controlled by various negative and pos itive regu lators , which p lay a critical role in chemoresistance (33).
The B-cell lymphoma 2 (Bcl-2) family of proteins consists of anti-apoptotic and pro-apoptotic proteins. The former includes B-cell lymphoma-extra-large (Bcl-xL), Bcl-2, and myeloid-cell leukemia 1 (Mcl-1), while the latter includes Bcl-2-associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), and BH3. Bak and Bax enhance the formation of MAC, while Mcl-1, Bcl-2, and Bcl-xL inhibit its formation (34). Apart from the established roles of Bak and Bax in apoptosis, the ratio of proapoptotic/anti-apoptotic proteins is what governs apoptosis, rather than individual protein expression. In cancer cells, the upregulation of anti-apoptotic mediators allows cells to evade apoptosis. This also allows cancer cells to escape apoptosis even when exposed to chemotherapeutic drugs, which would otherwise induce apoptosis in susceptible cells (35). Thus, dysregulation of the pro-apoptotic/anti-apoptotic protein ratio is another mechanism of chemotherapy resistance due to decreased apoptosis of cancer cells.
In cancer cells, the activities of both pro-and anti-apoptotic mediators are controlled by Jun amino terminal kinase (JNK) and p38-mitogen-activated protein kinase (MAPK). The latter increases p53 and apoptosis in chemoresistant cells through the protein kinase B (Akt)/Forkhead box O3 (FoxO) pathway. Insulin-like growth factor 1 suppresses apoptosis via casein kinase 2 and PI3K/Akt pathways, which in turn arrests Smac/ DIABLO release and suppresses caspase activity (36). In addition, p53 mutations reduce chemoresistance through modulatory roles on mitochondrial function, leading to increased chemosensitivity. The overexpression of tissue inhibitor of metalloproteinase-1 (TIMP) compromises chemotherapy response via NF-kB and PI3K/Akt signaling pathways (37). The actin-bundling protein, fascin, plays an important role in breast cancer chemoresistance by increasing the level of anti-apoptotic proteins and blocking the entry of the pro-apoptotic proteins caspase-3 and caspase-9 (37). Notch-1 and survivin are other signaling pathways that contribute to chemoresistance by activating targets involved in cell survival, thereby inhibiting apoptosis in tumor cells (38).
Other mechanisms of tumor resistance are related to dysregulated autophagy. Autophagy allows cells to regain ATP and vital biosynthetic factors in tumor microenvironments that are hypoxic and starved, promoting cancer cell survival. Autophagy acts as a critical modulator of intracellular hemostasis, tumor suppression, aging, cell death, and tumor chemoresistance (39). However, autophagy acts as a doubleedged sword, as it also plays a role in the initiation, growth, development, and invasion of tumor cells. Accordingly, the PI3K/Akt/mTOR signaling pathway plays a crucial role in autophagy by modulating cell growth, cell survival, protein synthesis, motility, cell metabolism, cell death, and chemoresistance (39). This also downregulates the proapoptotic mediators Bim and Bad (40). Apoptotic mediators and autophagy are also regulated by upstream JNK and p38MAPK, thereby playing a vital role in modulating chemoresistance (41). Many anticancer drugs disrupt the balance between autophagy and apoptosis by altering the genetic/epigenetic phenotype and inhibiting PI3K/Akt/mTOR in cancer cells, thereby leading to the development of chemoresistance (41).
Attenuation of immune checkpoints potentially stimulates regulatory T cells (Tregs), creating an immunosuppressive microenvironment and modulating autoantigenicity antigen shedding or endocytic antigens to mediate immune escape ( 45 ). Such conditions trigger the polariza tion of immunosuppressive cells, such as M2 macrophages, antigenpresenting cells (APCs), and myelocytes, producing immunosuppressive cytokines. This also stimulates T helper type 1 (TH1) and TH17-mediated inflammatory conditions to upregulate oncogenic pathways and accelerate tumor growth and immunotherapy resistance (43,46). Consequently, dendritic cells (DCs), B lymphocytes, monocyte-macrophages, and other APCs such as fibroblasts, endothelial cells, mesothelial cells, and epithelial cells are interconnected with tumor-specific antigen (TSA)/tumor-associated (TAA), conferring immunogenicity and T cell infiltration in tumors. Autophagy and the endoplasmic reticulum (ER) determine the tumor-associated immunogenicity of cell death (47). Dysregulation of antigen presenting signaling pathways, including mutations of the proteasome, transporters, and major histocompatibility complex (MHC), is cross-talked with T cell activity and tumor immune escape. MHC mutations are classified into structural defects, changes in the receptorbinding domain, and epigenetic changes (48). In some cancer types, tumor cells are able to escape lysis mediated by cytotoxic T lymphocytes (CTLs) and natural killer cells (NKs) through the overexpression of MHC-I. This allows tumor cells to escape the immune system (49).
The dysregulation of emerging signaling pathways in tumor cells is another mechanism of immunotherapy resistance. For instance, IFN-g, produced by T cells and APCs, binds to related receptors to activate JAK2 (50). This leads to interaction with STAT1, which modulates downstream cascades. IFN-g allows tumor cells to escape the immune system by increasing the expression of PD-L1 on the surface of tumor cells (51). IFN-g also upregulates C-X-C motif chemokine ligand (CXCL)-9 and CXCL-10 chemokines and promotes antitumor immune cell effects (51). Additionally, IFN-g exerts pro-apoptotic and antitumor properties through binding to cell surface receptors and triggering downstream mediators to suppress tumor cells (51). In patients receiving immunotherapeutic agents, tumor cells alter IFN-g and JAK/STAT1 signaling pathways. Tumor analysis of chemoresistant patients receiving anti-cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) agents had mutations in IFN-g pathway genes, JAK1/2, and interferon regulatory factors (52). This allowed tumor cells to evade T cells, thus resisting the anti-CTLA-4 treatment. Loss of polybromo and BRG1-associated factors (PBAF) complex increased the ability of chromatin to regulate IFN-g as well as increased production of CXCL-9/CXCL-10 to recruit T cells to tumor tissue (53). In human cancers, expression of Pbrm1 and Arid2 is correlated with the presentation of T cell cytotoxicity genes, leading to immunotherapy resistance (53). Spranger et al. (54) demonstrated that the infiltration of T cells and recruitment of DCs into the total mesorectal excision (TME) could be suppressed by tumor-intrinsic b-catenin activation via decreased expression of CCL4. Because DCs prevent migration into epithelial-to-mesenchymal transition (EMT), no antigen can be presented to T cells, halting their cytotoxic effects. From another mechanistic point, upregulation of MAPK signaling damages the function and infiltration of tumor-infiltrating lymphocytes through the expression of vascular endothelial growth factor (VEGF) and cytokines such as interleukin-8 (IL-8) (55). Under these conditions, induction of Tregs ultimately leads to tumor immune evasion. Loss of tumor suppressor phosphatase and tensin homolog (PTEN) leads to activation of PI3K signaling, which is associated with increased anti-inflammatory cytokines, such as VEGF and C-C motif chemokine ligand 2 (CCL2), reduced infiltration of CD8+ T cells into tumors, and decreased IFN-g expression, conferring resistance of PD-1 blockade therapy against tumors (56).
Tumor cells develop immunotherapy resistance by altering tumor cell metabolism through multiple metabolic changes, termed tumor metabolic reprogramming (57). One such mechanism utilizes aerobic glycolysis to create a hypoxic acidic environment which prevents normal metabolism of immune cells and impairs T cell function and infiltration (58). Furthermore, glucose consumed by tumor cells may restrict T cell metabolism, which leads to inhibition of mTOR, decreased glycolytic capacity in T cells, and production of intracellular IFN-g (59).

TLR/NF-kB/NLRP SIGNALING PATHWAY IN CANCER INITIATION AND PROGRESSION AND CHEMORESISTANCE
TLRs are members of the type I transmembrane proteins and are conserved pattern-recognition receptors (PRRs) that are activated by various pathogen-associated molecular patterns (PAMPs). These membrane proteins are heavily expressed on the surface of several cells, including monocytes, macrophages, and DCs. The three constructional domains of TLRs' include a leucine-rich repeats (LRRs) motif, a transmembrane domain, and a cytoplasmic domain. Each of these domains have a specific function. For example, pathogen recognition is performed by the LRR motif, while signal initiation is performed by interaction of the TIR domain with the signal transduction adaptors. This receptor family is extremely important for pathogen recognition by the innate immune system (60,61). Recently, several reports have indicated the association between cancer and TLRs. Specifically, the TLR4 signaling pathway is the most tightly linked with inflammatory response and cancer initiation and progression (16).
TLRs are involved in tumor progression, however they may display either anti-or pro-tumor metastasis and growth features (62). Activation of TLR4 increased IL-6 and IL-8 production in breast cancer (63). In some cancers, TLR4 induced the production of nitric oxide and IL-6 (64). In prostate cancer cells, TLR4 activation enhanced the expression of transforming growth factor-b1 (TGF-b1) and VEGF, which promoted tumor progression (65). Some studies have shown poorer outcomes for breast, colon, and pancreatic cancers when TLR4 is overexpressed (63,64). The myeloid differentiation factor 88 (MyD88) pathway of TLR4 has been shown to improve carcinogenesis. Yusef et al. (66) found that TLR4 demonstrated antitumor activity in skin cancer. The role of TLR4 should be further evaluated in various cancer types. Overall, these results suggest that the release of various inflammatory mediators, cytokines, and chemokines activates TLR4 and may participate in cancer formation.
TLRs are strong actuators of the inflammatory response, activation of which triggers the production of interferons, chemokines, cytokines, and NF-kB. The NF-kB pathway plays a crucial role in various diseases through regulation of cell proliferation, differentiation, immunity, and apoptosis (67). The NF-kB family consists of five crucial parts: p50, p52, p65/RelA, c-Rel, and RelA. NF-kB acts as a transcription factor by binding DNA, which activates gene transcription. Several genes involved in the progression and development of cancer are regulated by NF-kB, such as those involved in proliferation, apoptosis, and migration. Improper or constitutive NF-kB activation has been found in many malignant human tumors (68).
Typically, NF-kB is bound to IkB (IkB) in the cytoplasm. In times of stress, reactive oxygen species (ROS) and inflammatory stimuli degrade the IkB complex to activate NF-kB, releasing inflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), IL-1, IL-6, and IL-2. This inflammatory cascade suppresses apoptosis and induces cellular invasion, proliferation, and metastasis, aiding in chemoresistance [52]. Prevailing reports have shown that activation of NF-kB by tumors assists in the development of chemotherapy resistance. NF-kB activation plays a key role in hindering the effectiveness of chemotherapeutic agents. Tumor cells exposed to chemotherapeutic drugs or radiation showed increased activation of NF-kB, which enforced the expression of MDR Pgp. Meanwhile, NF-kB suppression improved the apoptotic response to radiation therapy (69).
Members of the NLR family play an essential role in the signaling pathways of the innate immune system by activating or inhibiting inflammasomes. Damage-associated molecular patterns (DAMPs) and PAMPs activate NLRs and absent in melanoma 2 (AIM-2)-like receptors (ALRs), which bind to associated cytosolic domains to activate caspases. As a result, caspases upregulate IL-18 and IL-1b, which results in apoptosis and pyroptosis (70). On the other hand, dysregulation of NLR contributes to various autoimmune and inflammatory diseases. Thus, NLR can play a role in tumor suppression or tumor promotion in the initiation, development, and regression of cancer (71). Therefore, targeting the TLR/NF-kB/NLRP signaling pathway may facilitate improvement in the regulation of cancer initiation/progression and associated chemoresistance.

TLR/NF-kB/NLRP SIGNALING PATHWAY IN CANCER IMMUNOTHERAPY
TLRs are part of a family of recognition receptors which play a pivotal role in the host immune system (72)(73)(74). TLRs are expressed by B cells, macrophages, monocytes, NK cells, mast cells, neutrophils, and basophils. TLRs stimulate pro-inflammatory chemokines and cytokines to activate the innate and adaptive immune systems. The activation of TLR4 can induce associated adaptor proteins, including MyD88, TIR domain-containing adapter molecule 1 (TICAM1), TIR domain-containing adapter molecule 2 (TICAM2), and TIR domain-containing adaptor protein (TIRAP). Some ligands (e.g., lipopolysaccharides and toxins) bind TLRs to activate the immune response. According to Nagai et al. (75), the co-receptor myeloid differentiation factor-2 (MD-2) increased the translocation of TLR4 to form a heterotrimer of CD14/TLR4/MD-2 (76). This may lead to two distinct signaling pathways, the MyD88 pathway and the toll/IL-1R domaincontaining adapter-inducing IFN-b (TRIF) pathway. Tumor necrosis factor receptor-associated factor 6 (TRAF6) activates extracellular signal-regulated kinase (ERK), MAPKs, and the p38 signaling pathway. Alternatively, TLR4 activates the MyD88independent pathway to upregulate NF-kB and suppress IkB kinase epsilon (IKK). MyD88-dependent and MyD88independent pathways also contribute to host defense and engage the immune response. In addition, TLRs activate IRFs, which increase the transcription of interferon-a (IFN-a) and interferonb (IFN-b) (77). NLRP is the downstream mediator of NF-kB, which is interconnected with the inflammasomes. Inflammasomes are receptors/sensors of the innate immune system that regulate caspase-1 activation in response to host-derived proteins. Accordingly, NLRP activates apoptosis cascades which contributes to cancer chemoresistance. Overall, TLR/NF-kB/ NLRP play critical roles in the development of cancer chemoresistance mediated by the attenuation of apoptosis, inflammation, oxidative stress, and autophagy. As shown in Figure 2, the immune system is also cross-talked with dysregulated major signaling pathways of chemoresistance.

METHODOLOGY FOR LITERATURE SEARCH ON THE EFFECT OF PHYTOCHEMICALS ON CHEMOTHERAPY AND IMMUNOTHERAPY RESISTANCE
We have performed a systematic review on vital mechanisms and the therapeutic potential of plant secondary metabolites in combating cancer chemoresistance utilizing the PRISMA guideline. Scholarly electronic databases, including Scopus, Science Direct, Cochrane, and PubMed, were used for the literature search. The search included all English language articles through October 30, 2021. The following keywords were used for the search: chemoresistance [full text] OR (cancer OR malignancy OR neoplasm OR melanoma OR leukemia OR carcinoma) [title/abstract] AND (nuclear factor kappa* OR NF-kB OR toll-like* OR nod-like receptor* OR NLRP) AND (chemotherapy OR chemoresistance OR immunotherapy OR chemo-therapy OR chemo-resistance OR immune-therapy) [title/abstract] AND (herb OR plant OR natural product OR secondary metabolite OR polyphenol* OR terpen* OR alkaloid* OR flavonoid* OR glucosinolate* OR coumarin*). Two independent authors (S.F. and S.Z.M.) designed and applied the search strategy, which was finalized by the senior author (A.B.).
Of the initial 1392 articles, 205 articles were excluded due to duplicated results, 297 articles were excluded as they were review articles, 691 articles were excluded according to their title/ abstract, 229 articles were excluded according to their full text information, and 4 articles were omitted since they were not in English. Ultimately, 267 articles were included in this systematic review. Figure 3 depicts the PRISMA flowchart, which displays the literature search process and selection of relevant studies.

MULTI-TARGETING PHYTOCHEMICALS IN CANCER THERAPY
Plant secondary metabolites are potential modulators of multiple dysregulated pathways due to their various pharmacological properties, including antioxidant, anti-inflammatory, and anticancer effects (78,79). An increasing number of pre-clinical and clinical studies have shown that chemopreventive agents may regulate the aforementioned dysregulated signaling pathways, such as TLR, NF-kB, and NLRP, thereby preventing or treating multiple cancer complications (16). Considering the critical role of TLR/NF-kB/NLRP in the progression of chemotherapy and immunotherapy resistance, discovering multi-targeting therapeutic agents could assist in combating cancer chemoresistance and immunoresistance. Several reports have addressed the potential of phytochemicals in the attenuation of TLR/NF-kB/NLRP. Therefore, phenolic compounds, alkaloids, terpenes/terpenoids, and sulfur compounds have been proposed as potential agents in the prevention and treatment of chemoresistance and immunoresistance.
Gallic acid is a natural antioxidant found in various fruits and tea leaves that belongs to the polyphenolic class of secondary metabolites. Various pharmacological effects of gallic acid include antioxidant, anti-inflammatory, and antineoplastic activities. There have been multiple studies which report that gallic acid ( Figure 4) inhibited the progression of T24 and AGS gastric cancer cells via suppression of PI3K/Akt/NF-kB signaling and promotion of mitochondrial dysfunction (125,126). Furthermore, quercetin inhibited the invasion and migration of Caco-2 cells via regulation of the TLR4/NF-kB pathway and decreasing MMP-2 and MMP-9 (127). In a similar study, inhibition of NF-kB, p53 induction, apoptosis, and cell cycle arrest were reported as the primary anticancer mechanisms of quercetin against the HeLa cervical cancer cell line (128). Additionally, quercetin showed antitumor activity against lung (A549 and H460) (129,130), prostate (PC3 and LNCaP) (131), breast (MCF-7) (132), and oral SCC (133) cancer cells via induction of apoptosis and downregulation of IL-6/STAT-3 and NF-kB. The results demonstrated that combination of quercetin with chrysin suppressed the migration and invasion of nickel via downregulation of TLR4/NF-kB signaling in human lung cancer cells in vitro (134). Octyl gallate exerted significant efficacy against heat shock protein 90a (HSP90a) levels, eHSP90a-TLR4 ligation, M2-macrophages, and tumor growth in a pancreatic ductal adenocarcinoma mouse model (135).
In summary, polyphenols play a significant role in the prevention and treatment of cancer. Curcumin, apigenin, quercetin, and resveratrol are the most important polyphenols with reported information on their mechanisms of action and clinical trials. In several reported studies, polyphenols can interfere with a variety of anticancer pathways, including TLR/NF-kB/ NLRP and interconnected pathways. Consequently, polyphenols could be considered promising treatment options in conjunction with other cancer treatment strategies. Table 1 provides the various anticancer phenolic compounds that interfere with the TLR/NF-kB/NLRP pathway to combat chemoresistance.

Terpenes and Terpenoids
Terpenes and terpenoids represent large classes of natural products isolated from multiple vegetative sources. These phytochemicals exert several therapeutic effects, including anticancer, cardioprotective, neuroprotective, and hepatoprotective activities. Each terpene/ terpenoid compound is composed of several isoprenes (a fivecarbon unit) that are assembled in thousands of ways. Zerumbone ( Figure 5), an important sesquiterpene isolated from ginger, suppressed lung and colon tumors in mice via induction of apoptosis and inhibition of proliferation, heme oxygenase 1 (HO-1), and NF-kB expression (216). Andrographolide ( Figure 5) is a bioactive phytochemical obtained from Andrographis paniculata that belongs to the diterpenoid compounds. Likewise, andrographolide showed antitumor activity against B16 melanoma cells, C57BL/6J mice (217), and RIP1-Tag2 mice (218) via suppression of TLR4/NF-kB signaling, thereby reducing the expression of CXCR4 and Bcl-6. Additionally, treatment with andrographolide inhibited the proliferation of SW620 colon cancer cells in vitro via interfering with the TLR4/NF-kB/MMP-9 signaling pathway (219).
In a similar study, ursolic acid demonstrated significant in vitro and in vivo anticancer activity against DU145 and LNCaP prostate adenocarcinoma cells, as well as a mouse model via diminished CXCR4/CXCL-12 signaling axis and reduced activation of NF-kB (228). Furthermore, ursolic acid induced apoptosis and inhibited growth in several in vitro pancreatic and colon cancer models by interfering with PI3K/Akt/NF-kB, STAT, GSK, TRAIL, and JNK pathways (229,230). In addition to ursolic acid, heteronemin ( Figure 5) showed significant antiproliferative effects against AML cells via targeting NF-kB, Ras, MAPK, AP-1, and c-myc (231). Soyasaponins, bioactive phytochemicals found in a multitude of legumes, downregulated TLR4/MyD88 signaling and decreased TNF-a, IL-6, COX-2, NO, IL-1b, and iNOS in inflammatory macrophages (232). Oleanolic acid ( Figure 5), another triterpenoid structure, and its synthetic derivative SZC014 showed considerable antitumor effects against the hepatocellular cancer cell lines HepG2, interfering with NF-kB and nuclear factor-erythroid factor 2-related factor 2 (Nrf-2)/ antioxidant response element (ARE) signaling (233,234). Additionally, inhibition of IkB kinase and suppression of NF-kB signaling are the primary anticancer mechanisms of lycopene ( Figure 5) in breast and prostate cancer cells (235). The monoterpene geraniol ( Figure 5) is an acyclic isoprenoid derived from essential oils. Geraniol attenuated tongue carcinogenesis via decreased activation of NF-kB (236). Additionally, the NF-kB and STAT3 pathways are the chemopreventive mechanisms of andrographolide via inhibition of inflammatory mediators (237). Moreover, treatment with celastrol ( Figure 5) downregulated NF-kB and reduced the expression of IL-6 in prostate and breast cancer cells (238,239). In a similar study, actein ( Figure 5) strongly suppressed the growth of MDA-MB-453 cells by enhancing the cytoplasmic calcium and modulating the MAPK/ERK kinase (MEK) and NF-kB pathways (240).
Diosgenin ( Figure 5), a known steroidal triterpenoid with two pentacyclic rings, is found in Trigonella foenum graecum (241). Progesterone, pregnenolone, cortisone, and other steroids can be synthesized from diosgenin, which comprises more than 60% of commercial synthetic steroids (242). Diosgenin has shown several biological activities, including anticancer, antidiabetic, antiinfectious, anti-inflammatory, and anticoagulant effects (242).  Diosgenin exerted significant antitumor potential via induction of apoptosis and suppression of inflammation. It also inhibited the invasion, metastasis, angiogenesis, and proliferation of various cancer cell lines. Accordingly, targeting inflammation-related pathways, including NF-kB and STAT3, is one of the main anticarcinogenic mechanisms of diosgenin (241,242). Diosgenin displayed antiproliferative effects in HEp-2 and M4Beu cell lines via enhancing the production and release of apoptosis-inducing factors, increasing the Bax/Bcl-2 ratio, modulating caspase-3, and facilitating the activation of p53 (243). Furthermore, diosgenin induced apoptosis in the colon cancer cell lines HT-29 and HCT-116 in vitro by interfering with COX-2 signaling and increasing DNA fragmentation, caspase-3, and 5-lipoxygenase activity (244). Additionally, diosgenin sensitized colorectal cancer cells to apoptosis induced by TRAIL via activation of the p38MAPK pathway, overexpression of death receptor-5 (DR5), and downregulation of the Akt pathway (245). Several compounds belonging to the terpenes and terpenoids classes exhibit antineoplastic properties by affecting various stages of tumor development, including suppression of the initiation and progression of tumorigenesis through promoting apoptosis, cell cycle arrest, inhibition of metastasis, angiogenesis, invasion, and downregulation of several intracellular signaling pathways, including TLR4, STAT3, NF-kB, and MMP-9. These compounds are promising therapeutic agents due to the massive progression in delineating the details of their anticancer action. Table 2 provides the various anticancer terpenes/terpenoids that interfere with the TLR/NF-kB/NLRP pathway to counter chemoresistance.
Ulmus davidiana Nakai glycoprotein (303), phenylpropenone derivatives (304), libanoridin (305), and alisol B 23-acetate (306)  Overall, sulfur-containing compounds demonstrate critical biological properties and therefore have meaningful potential for the prevention and treatment of cancers. These phytochemicals could target multiple signals affecting cancer progression, especially TLR/NF-kB/NLRP signaling and cross-talked pathways, to support cancer immunotherapy and chemotherapy. Table 4 provides the various anticancer sulfur and miscellaneous

PHYTOCHEMICALS IN COMBINATION WITH ANTICANCER DRUGS POTENTIATE CHEMOTHERAPY AND IMMUNOTHERAPY
Despite the recent progress in designing, synthesizing, and introducing new pharmaceutical drugs, natural products and bioactive molecules isolated from plants exert undeniable roles in the treatment of various cancers. Currently, the most important treatment option for malignant tumors is chemotherapy, which may lead to numerous side effects and promote drug resistance in patients. The use of natural products for the treatment of cancer is not only economically efficient, but also exerts multiple prophylactic, protective, and therapeutic roles in the treatment process that may reduce the side effects of chemotherapy and radiotherapy and decrease drug resistance (6,13,(324)(325)(326). Numerous studies have investigated the in vitro and in vivo advantages of adding curcumin to various anticancer treatment regimens. Liposomal curcumin has sensitized mouse models of cervical cancer to paclitaxel treatment (327). Curcumin also facilitated the induction of cell death by paclitaxel in MCF7 and MDA-MB-234 cell lines (328,329). It was reported that curcumin induced cell apoptosis and increased paclitaxel sensitivity in cervical cancer cells through interfering with NF-kB, p53, and caspase-3 signaling (330). In similar studies, curcumin significantly sensitized breast cancer cells to cyclophosphamide and paclitaxel through modulation of NF-kB, protein kinase C (PKC), histone deacetylase (HDAC), and telomerase (331). Combining curcumin with oxaliplatin reversed the acquired resistance in an in vitro model of colorectal cancer by interfering with the CXC-chemokine/NF-kB pathway (332). In addition, curcumin increased the chemosensitivity of several platinum-based drugs via arresting the cell cycle in the G2/M phase, inducing apoptosis, and downregulating NF-kB (333). Similarly, co-delivery of curcumin and dasatinib led to the enhanced antitumor activity of dasatinib against colon cancer cells via diminished insulin-like growth factor type 1 receptor, c-Src, and EGFR signaling (334). Moreover, curcumin worked synergistically with tamoxifen to suppress the growth of MCF-7/LCC9 and MCF-7/LCC2 cells in an in vitro model of breast cancer by facilitating cell cycle arrest and inactivating the Akt/ mTOR, Src, and NF-kB pathways (335). Furthermore, curcumin sensitized MDA-MB-231 cells to retinoic acid (336) and enhanced the efficacy, as well as diminished the toxicity, of doxorubicin (337). The anticancer potential of sorafenib against Huh7 cells and an athymic mice model of hepatocellular carcinoma was enhanced when combined with curcumin as evident by decreased expression of MMP-9 and NF-kB/p65 (338). Another well-known polyphenolic compound, resveratrol, sensitized PC3 and DU145 prostate cancer cells in vitro to cisplatin-induced apoptosis via inhibition of COX-2 and NF-kB pathways (339). In a similar study, resveratrol significantly increased the efficacy of cisplatin in xenografted mice and MDA-MB-231 cancer cells via decreased activity of p-ERK, TGF-b1, Smad2, vimentin, p-Akt, NF-kB, p-PI3K, and p-JNK (340). Furthermore, resveratrol sensitized colorectal cancer cells to 5fluorouracil (5-FU) by inducing apoptosis and downregulating NF-kB (341). Additionally, resveratrol improved the gemcitabine-induced apoptosis of PaCa cells via inhibition of NF-kB and diminished expression of cyclin D1, VEGF, intercellular adhesion molecule-1 (ICAM-1), COX-2, and MMP-9 (342). Apigenin is another polyphenolic substance that potentiated the antitumor activity of several antineoplastic agents, including paclitaxel (343), tamoxifen (344), gemcitabine (345,346), doxorubicin (347), and cisplatin (348) against various in vitro and in vivo cancer models. Polyphenol quercetin is another anticancer compound that works synergistically with paclitaxel (349,350), tamoxifen (351), cisplatin (352,353), adriamycin (354), and gemcitabine (355) to suppress the growth of various models of cancer via enhanced ROS production, cell cycle arrest, ER stress, and apoptosis. Similarly, various studies have reported the advantages of adding EGCG to enhance the antitumor activity of sunitinib, irinotecan, doxorubicin, gemcitabine, and cisplatin against human lung (A549, H460, and H1975) (356,357), colorectal (HCT116 and RKO) (358), bladder (SW780 and   with doxorubicin (362) and paclitaxel (363) amplified their anticancer activity against human esophageal and prostate cancer cells, respectively. Moreover, baicalin improved the chemosensitivity to cisplatin (364) and doxorubicin (365) in lung and breast cancer cells, respectively, by inducing cell cycle arrest, apoptosis, and DNA damage. Furthermore, arctigenin sensitized various cancer cell lines, including SW620, HepG2, H460, HeLa, SW480, and K562, to cisplatin treatment (366)(367)(368). Morin (369), chrysin (370), and pterostilbene (371) are some of the other polyphenolic compounds that increased the cytotoxicity of antineoplastic agents in several in vitro models of cancer. In addition to polyphenols, terpenes also showed a significant ability to increase the sensitivity of different cancer cell lines to various drugs, such as 5-FU, gefitinib, cisplatin, doxorubicin, and gemcitabine. Combination therapy of cisplatin and paclitaxel with zerumbone, a sesquiterpene agent, enhanced ROS production and p53 expression, as well as inhibited the JAK2/ STAT3 pathway in prostate and lung cancer cells (372,373). It was reported that andrographolide augmented the doxorubicinmediated antitumor activity in different cancer cells through the blockade of JAK/STAT3 signaling (374,375) and its coadministration with gemcitabine promoted apoptosis and inhibited STAT3 in pancreatic cancer cells (376). Furthermore, treatment with andrographolide increased cisplatin-induced antineoplastic activity against lung cancer cells (377). Carnosic acid is another triterpenoid compound that, in combination with cisplatin and tamoxifen, promoted apoptosis in lung (378) and breast (379) cancer cells. In addition to carnosic acid, triptolide showed significant anticancer properties and amplified the in vitro and in vivo anticancer activity of various chemotherapeutic agents, including cisplatin (380)(381)(382), paclitaxel (383), hydroxycamptothecin (384,385), gemcitabine (386), and doxorubicin (387), in several cancer types, including bladder (EJ, UMUC3, and T24R2), breast (MDA-MB-231, BT549, and MCF7), lung (A549), and gastric (SC-M1) cancer cell lines. Another triterpenoid compound, ursolic acid, potentiated the therapeutic effects of gemcitabine, oxaliplatin, cisplatin, and paclitaxel in human pancreatic and colorectal cancer cells by promoting apoptosis and inhibiting the inflammatory microenvironment and NF-kB p65 signaling (388)(389)(390)(391). Moreover, treatment with oridonin overcame antibiotic resistance and augmented the antineoplastic effects of doxorubicin, cisplatin, and gemcitabine via increased expression of Bax, induction of apoptosis, downregulation of Bcl−2, and inhibition of MMP in the in vivo and in vitro models of lung, breast, pancreatic, and ovarian cancers (392)(393)(394)(395). In a similar study, ginsenoside Rg3 enhanced the cytotoxicity of paclitaxel in breast cancer cells by regulating the expression of Bax/Bcl-2 and suppressing NF-kB signaling (396). Additionally, ginsenoside Rg3 amplified cisplatin therapy in the lung cancer cell lines H1299, SPC-A1, and A549 by inhibiting the NF-kB pathway (397,398). Another study found that co-administration of ginsenoside Rg3 and gefitinib increased the cytotoxicity of gefitinib against lung cancer in vitro (399). The results demonstrated that the main mechanisms by which ginsenoside Ro enhances the anti-malignant effects of 5-FU occurs by accumulating DNA damage, inhibiting DNA repair, downregulating DNA replication, and delaying the degradation of checkpoint kinase 1 (CHEK1) (400). The treatment combination of docetaxel and ginsenoside Rg3 increased activation of the apoptotic pathway in colon and prostate cancer cells via suppression of NF-kB (401,402). Lycopene, a carotenoid agent, improved cisplatin-induced apoptosis in HeLa cancer cells via inhibition of NF-kB activation (403).
Alkaloids, like other secondary metabolites, enhance the in vitro and in vivo anticancer activities of various drugs by elevating their antiproliferative effects and promoting apoptosis and cell cycle arrest. The combined effects of doxorubicin and berberine on lung (404) and breast (405,406) cancer cells inhibited the STAT3, high mobility group box 1 (HMGB1)-TLR4 axis and downregulated the expression of Nanog and miRNA-21. Cisplatin and berberine combined therapy also inhibited cell growth, promoted apoptosis, created DNA breaks, and interfered with miR-93/PTEN/Akt signaling in MCF-7 and A2780 cells (407,408). Moreover, berberine increased the chemotherapy potential of irinotecan against in vitro models of colon cancer through the suppression of NF-kB (409). Another alkaloid compound, piperlongumine, induced apoptosis and potentiated the anticarcinogenic activity of doxorubicin, paclitaxel, oxaliplatin, cisplatin, and gemcitabine via suppression of the JAK2/STAT3 pathway and induction of oxidative stress in breast, intestinal, gastric, HNSCC, colorectal, and pancreatic cancer cells (410)(411)(412)(413)(414)(415). In a similar study, harmine, in combination with paclitaxel, suppressed the invasion and migration of SGC-7901 and MKN-45 gastric cancer cell lines via downregulation of MMP-9 and COX-2 (416,417). In addition, harmine suppressed the proliferation of pancreatic cancer cells in vitro by enhancing the cytotoxicity of gemcitabine (418). Likewise, several studies have reported the advantages of combining matrine with irinotecan and cisplatin to augment their antitumor activity against human colorectal (HT29) (419), urothelial bladder (EJ and T24) (420), liver (HepG2) (421), and cervical (U14) (422) cancer cell lines. The results suggested that matrine significantly potentiated the antineoplastic effects of both irinotecan and cisplatin and increased the sensitivity of the aforementioned cancer cells to treatment through induction of apoptosis, facilitation of cell cycle arrest, and enhanced activity of topoisomerase I, ROS, b−catenin, Bax, caspase-3, caspase-7, and caspase-9. Treatment with sophoridine inhibited the growth of lung cancer cells by amplifying cisplatin sensitivity via activation of Hippo and p53 signaling (423). Sulforaphane could significantly sensitize human breast, lung, colorectal, and bladder cancer cells to variant chemotherapeutic agents via downregulation of NF-kB, induction of cell cycle arrest, and reduction of cyclin A and p-Akt (424)(425)(426)(427). Furthermore, sulforaphane increased the in vitro and in vivo antiproliferative activity of salinomycin in colorectal cancer cells via diminished signaling of the PI3K/Akt pathway (428). Moreover, shikonin reversed gemcitabine tolerance in a xenograft model of pancreatic cancer via modulation of the NF-kB signaling pathway (429). Treatment with shikonin potentiated the antitumor efficacy of gefitinib in lung cancer cells through suppression of the PKM2/STAT3/cyclin D1 pathway (430). Shikonin also increased the sensitization of paclitaxel against esophageal cancer cells by promoting apoptosis (431). Additionally, shikonin enhanced 4hydroxytamoxifen-induced apoptosis in breast cancer cells by activating mechanisms involved in apoptosis and its related signaling pathways (432). It was reported that co-treatment of breast cancer cells with phenethyl isothiocyanate and paclitaxel induced apoptosis, arrested the cell cycle, and inhibited cell growth (433,434). Garcinol induced the death of the breast cancer cell lines MCF7, MDAMB231, and SKBR3 via triggering p53-dependent upregulation of Bax and downregulation of Bcl-xL (435). It also potentiated cisplatin sensitivity in HNSCC (436) and ovarian (437) cancer cells, as well as enhanced paclitaxel sensitivity in breast cancer cells (438) via inhibition of survivin, NF-kB/Twist-related protein 1 (Twist1), VEGF, caspase-3/ calcium-independent phospholipase A2 (iPLA2), cyclin D1, Bcl-2, and PI3K/Akt signaling.
In summary, phytochemicals have the potential to increase the sensitivity of various cancer cells and animal tumor models to several anticancer drugs. Phytochemicals augment chemoresistance through interfering with many processes, such as cell cycle arrest, DNA damage, angiogenesis, and variant signaling pathways, especially TLR/NF-kB/NLRP ( Table 5).

NANOFORMULATIONS OF PHYTOCHEMICALS AGAINST CHEMORESISTANCE AND IMMUNOTHERAPY RESISTANCE
Mutations and long-term chemotherapy lead to the development of chemoresistance, prompting the need for progressively increasing dosages of anticancer drugs. Consequently, these higher concentrations of chemotherapeutic agents are toxic to noncancerous cells (457). Nanoparticles are increasingly used due to their improved bioavailability, protection of drug molecules, high specificity for cancer cells, and decreased clearance. Combining the versatile capabilities of nanoparticles with the aforementioned benefits of phytochemicals created the concept of phytonanomedicine, which revolutionized cancer therapy (458). Phytonanomedicine utilizes the valuable properties of phytochemicals merged with the nano-size, high surface area, optical activity, and surface reactivity of nanoparticles to achieve active or passive tissue-specific drug delivery. The application of phytonanocompounds may reduce the toxicity and side effects of chemotherapeutic agents, while increasing their efficacy, thereby combating chemoresistance (459).
Flavones are the most prominent natural phytochemical that regulates the functions of Bax, Bid, and Bak proteins. Additional mechanisms by which phytochemicals combat chemoresistance are altering the expression of selected genes during mitosis or meiosis, regulating the expression of mutated genes like p21 and p53, and interfering with DNA repair mechanisms. Liposomes, polymeric nanoparticles, polymeric micelles, nanodispersion, and dendrimers, among others, are efficient nanocarriers that are often used (460).
Quercetin-loaded mesoporous silica decorated with chondroitin sulfate potentiated the delivery of paclitaxel,    overcoming MDR in breast cancer cells. Such co-administration successfully targeted CD44 receptor-mediated targeting with a low half-maximal inhibitory concentration (IC 50 ) value by increasing cell cycle arrest in the G2/M phase and destroying microtubules. Quercetin also decreased paclitaxel efflux by downregulating the expression of P-gp (349). In another study, Zafar et al. (461) used phosphorylated chitosan nanoparticles loaded with a-lipoic acid to overcome chemotherapy resistance.
The nanodelivery system was able to cross the cell barrier and expose the MDA-MB-231 cells to a high load of the therapeutic agent. Similar nanoparticles were also used for loading quercetin and paclitaxel simultaneously (462). The efficacy of curcumin and temozolomide co-delivery to chemoresistant cells was highlighted by Bagherian et al. (458). In this study, the curcumin nanomicelles demonstrated high cytotoxic effects against U87 cells by attenuating apoptotic and autophagic mediators. Zafar et al. (461) also used a phytochemical, thymoquinone, to prevent chemoresistance to docetaxel (e.g., endosomes escape). The neoplastic agent was loaded in chitosan nanoparticles and exhibited cytotoxicity against MCF-7 and MDA-MAB-231 cancer cell lines. Recently, a functionalized dendrimer has also been employed to co-deliver siRNA and curcumin to target HeLa cancer cells. Such co-administration increased the cytotoxicity against cancer cells by reducing Bcl-2 and improving apoptosis (463). Baicalein nanoparticles targeted folate and hyaluronic acid to display anticancer effects on paclitaxel-resistant lung cancer cells by decreasing tumor growth and cell viability (464). The nanosuspension of another flavonoid, chrysin, showed anticancer effects against HepG2 cells by blocking cell growth (465). The phytosome of luteolin, another flavonoid, exhibited anticancer activity against MDA-MB-231 cells by reducing the expression of Nrf-2/HO-1 and decreasing cell viability (466). Poly-lactic acid (PLA)-polyethylene glycol (PEG) nanoformulation of luteolin also demonstrated anticancer effects against TU212 HNSCC cells, H292 lung cancer cells, and a xenograft mouse model of head and neck cancer (467). Nanostructured lipid carriers were also used for dual drug loading of imatinib and curcumin to target the CD20 receptor of lymphoma cells. This co-delivery system displayed promising responses in resistant tumor cells (468). By regulating oxidative stress and apoptosis, phyto-nanocomposites diffuse into the organelles of cancer cells and overcome chemoresistance through multiple signaling pathways, including TLR/NF-kB/ NLRP, ERK/MAPK/JNK, stress-activated protein kinase/JNK, TRAIL, PI3K/Akt, and p53/caspase mediated apoptotic pathways (469).
A nanoformulation of honokiol, a lignan, showed anticancer effects in lung cancer cell lines by inducing cell cycle arrest in the G0/G1 phase (459). Silver nanoparticles of plumbagin, a naphthoquinone, induced apoptosis in the human skin cancer cells HaCaT and A431, producing free radicals and increasing pyruvate kinase activity (472). Liposomal phytochemicals may possess anticancer effects in intravenous usage. The liposomal carrier significantly increased plasma levels of curcumin in a dose-dependent manner in cancer patients. In one clinical study, liposomal curcumin showed acceptable plasma concentration with a significant but temporary decrease in tumor markers such as prostate-specific antigen and carcinoembryonic antigen, in patients with metastatic tumors. Additionally, liposomal curcumin inhibited sphingosine kinase (473). Lipocurcumin is known to be a safe drug that significantly suppresses cancer markers via apoptosis and cell cycle arrest. The curcumin nanoparticle suppressed STAT3/NF-kB, thereby inducing apoptosis. Accordingly, the phase Ib/IIa clinical trial showed no drug-related severe toxicity while maintaining an inhibitory effect on cancer resistance. Such nanoparticles could target cancer-specific mediators in solid tumors (473). The hyaluronic acid-modified PEGylated liposomes of doxorubicin-stigmasterol were used against chemoresistant breast cancer (474). Gold nanoparticles have shown promising potential in both cancer chemotherapy and immunotherapy (475). Resveratrol gold nanoparticles improved antitumor activity through mitochondrial accumulation and apoptosis both in vitro and in vivo. Gold nanoresveratrol also elevated the expression of caspase-8 and Bax, while reducing pro-caspase-3 and pro-caspase-9. Ginseng-derived nanoparticles are another phytonanocompound that induced M2 to M1 macrophage polarization through TLR4 and MyD88 signaling. It also produced ROS and increased apoptosis of melanoma cells (476).
Various nanoparticles may represent a novel class of nano-targeted systems in cancer immunotherapy and chemotherapy ( Table 6).

CONCLUSION, CURRENT LIMITATIONS, AND FUTURE PERSPECTIVES
Agrowing number of reports have highlighted the difficulty of chemoresistance when administering chemotherapy and immunotherapy. Several complex pathophysiological mechanisms behind chemoresistance have been discovered. Of those mechanisms, TLR/NF-kB/NLRP has been identified as a crucial aspect in the development of chemoresistance. The TLR/ NF-kB/NLRP pathway is interconnected with several inflammatory, oxidative stress, and apoptotic mediators. Thus, there is an urgent need to develop novel multi-targeted agents to overcome drug resistance and restore the sensitivity of current chemotherapeutic drugs. Plant secondary metabolites (e.g., polyphenols, alkaloids, terpenes/terpenoids, and sulfur compounds) are potential multi-targeted anticancer agents that may combat chemoresistant dysregulated mediators. We have also reviewed the potential of phytochemicals in the modulation of the tumor microenvironment (13,33,480). Despite the effectiveness of plant secondary metabolites in regulating chemoresistance-associated pathways, their low solubility, poor bioavailability, instability, and low selectivity limit clinical efficacy and therapeutic uses in cancer treatment. The applicability of nanotechnology has greatly improved bioavailability, cellular uptake, efficacy, and specificity of anticancer phytochemicals, thereby overcome those pharmacokinetic limitations (6,13,457,481). In line with this, liposomes, polymeric nanoparticles, micelles, nanodispersion, nanostructured lipid carriers, and dendrimers of plant secondary metabolites have played pivotal roles in reducing chemoresistance (482). In this systematic and comprehensive review, the critical roles of phytochemicals have been highlighted in the modulation of TLR/NF-kB/NLRP to combat chemoresistance. The need to develop novel delivery systems of plant secondary metabolites and targeted therapy is also highlighted. Further research should be performed involving additional dysregulated mechanisms in chemoresistance which may reshape therapeutic approaches to utilize plant-derived secondary metabolites (Figure 8). Additional studies should consist of extensive in vitro and in vivo experimentation to further unveil emergent chemoresistance signaling pathways, as well as well-controlled clinical trials. Such reports may reform current therapeutic strategies, allowing treatment methods to obtain higher potency/efficacy with fewer side effects and less chemoresistance by using phytochemicals that target the TLR/NF-kB/NLRP signaling pathway.

DATA AVAILABILITY STATEMENT
The original contributions presented in this study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS
Conceptualization, AB and SF. Literature search and collection: SF, SM, AY, and FN. Writing-original draft: SF, SM, AY, and FN. Writing-review and editing, SF, CW, and AB. Supervision: AB. Project administration: AB. All authors contributed to the article and approved the submitted version.