Sluggish immune responses are not optimal either, as those who are immunosuppressed may not be able to produce enough inflammation or effectively coordinate the biochemical reactions needed to clear an infection.

Fighting a virus takes a fine-tuned immune system—one that can launch a strong attack at the first sign of infection, but also knows when to scale down the attack once the virus subsides. The ultimate goal when attempting to achieve optimal immune health is to have a well-balanced immune system that responds appropriately when challenged.

Curcumin is a group of compounds curcuminoids derived from the root of the turmeric plant Curcuma longa. Since its discovery roughly two centuries ago, curcumin has become one of the most well-researched natural therapeutic ingredients.

Several factors, such as chronic stress, vitamin deficiencies, lack of sleep , and exposure to toxins, can impair the immune system. Unfortunately, chronic stress can overstimulate these innate immune cells, which may, in turn, suppress other components of the immune system responsible for controlling viruses.

Research has shown that those who have higher stress levels also have reduced antibody responses to influenza vaccination. Further support for the relationship between stress and immunity comes from studies reporting that psychological stress and negative mood states are associated with an increased vulnerability to infectious disease.

Many other factors can also cause the immune system to go haywire. For example, sleep deprivation can cause excessive activation of the innate immune cells, while at the same time, decreasing antiviral activity. As mentioned, our bodies react to a variety of factors that can cause innate immune cells to excessively activate.

Unfortunately, hyperactivation of these innate cell types results in the excessive production of acute-phase proteins , which can be damaging to our health. Additionally, chronic activation of these proteins may result in the suppression of antiviral defenses.

Prebiotics are non-digestible food substances that are consumed by health-promoting bacteria probiotics. The results of this study indicated that while the placebo group had reductions in gut flora species, curcumin and turmeric supplemented groups experienced increases in several types of gut bacterial species.

As mentioned, chronic stress and poor mood states are associated with suppressed antiviral responses and increased vulnerability to infections. Because all immune cells contain cortisol receptors, chronic stress may alter cortisol levels and impair immune responses.

When acute-phase proteins enter the blood, they can make their way into the brain. Once these proteins interact within the brain, a signal is sent to the adrenal glands to release cortisol.

Because omega-3s can make their way into the membranes of immune cells, it is thought that omega-3s can alter immune cell activity. Curcumin appears to have immune-balancing properties that may be particularly helpful for those with chronic stress. Additionally, curcumin may help promote optimal immune responses through its prebiotic-like properties, omega-3 boosting ability, and cortisol-lowering effects.

The key step of the immune escaping strategy of tumor cells is the conversion of the immunogenic TME into tolerogenic nature Figure 2 Most common immune evasion strategies by tumor cells: i Secretion of immune-suppressor molecules i.

In the TME, tumor cells implement numerous tactics to dodge the immune system and, therefore, establish a tolerogenic environment. It is already established that tumor TAAs are not necessarily neo-antigens that are specifically expressed in tumor cells; rather, they are tissue differentiation antigens that are also expressed in certain healthy cells and create an issue to generate an immune response against such tumor antigens During the late metastasis phase, efficient TAAs release generates effective immunity, but an immune tolerance has been already developed to TAAs by the time and antagonized the function of APCs and other effector T cells Tumor cells also sidestep T cell-mediated immune response by damaging antigen-presenting machinery.

Numerous genetic tumor variants by high-frequency mutation result in an escape from immune attack until some antigens are presented by stromal cells and cross-reacted with CTLs for the elimination A large number of tolerogenic cells like Tregs, tumor-associated macrophage TAM , and tolerogenic DC have been found in the TME.

These tolerogenic immune cells release some immunomodulatory molecules, such as TGFβ, IL, and PEG2, which foster a tolerogenic environment and block effector immune responses against the tumor growth In general, activated DCs generate effective co-stimulatory signals to T cells by secreting effector cytokines that stimulate T cells, further leading to tumor cell extinction However, in the TME, tumor cells release various immunosuppressive cytokines that alter immunogenic DCs to tolerogenic.

In addition, depletion of toll-like receptor-9 TLR9 and reduced IFNα secretion by pDCs have been recorded in the TME.

This phenomenon aids tumor antigens to escape immune surveillance Macrophages and other APCs play a very malicious role both in the case of tumor growth and regression simultaneously.

M1 macrophages exhibit a tumor-suppressive role with killing property, whereas M2 macrophages exhibit an immune-suppressive role with healing phenotype. Tumor-associated macrophages TAMs are mainly of M2 phenotypes. They gather in tumor sites and secrete growth-promoting factors like VEGF and EGF.

Macrophages also release TGFβ and IL, which cause the alteration of effector T cells into Treg cells and also induce immune tolerance Myeloid-derived suppressor cells or MDSCs have the tendency to accumulate around the tumor site and cause severe immunosuppression.

There are two general types of pathological MDSCs: monocytic MDSCs and polymorphonuclear MDSCs. In the absence of tumor-derived factors, the monocytic MDSCs and polymorphonuclear MDSCs both turn into macrophages, DCs and neutrophils, respectively. However, the presence of tumor-derived soluble factors induces the formation of immunosuppressive macrophages, TAM, and tolerogenic DC, respectively Its interaction with cancer cells decides its competition or cooperation and, accordingly, the suppression and promotion of further tumor progression.

It is a thick stromal layer surrounding the malignant tissues and composed of non-malignant cellular and non-cellular connective tissues 25 , The components of stroma are extracellular matrix ECM , fibroblasts, mesenchymal stromal cells, osteoblasts, and chondrocytes These interactions have been involved in the alteration of the genotype and phenotype of cancer cells and create physical barriers with hypoxic condition and abnormal vascularization, which promote tumor growth While potential immune cells are prevented to penetrate the tumor mass, the growing blood vessels help in metastasis, and the efficient release of TAAs in draining lymph nodes is also prevented by stromal cells 9.

These stromal layers have a deep impact on tumor therapy. It acts as a tough barrier for therapeutic agents by limiting their access to the target tissues and by degrading the drugs by stromal enzymes Chemo- and radiotherapy induce DNA damage in TME, which raises stress response in stromal cells.

This stress response accelerates the secretion of biomolecules, which promote cancer cell survival, proliferation, and metastasis 30 , Stromal cells make cancer cell immunotherapy resistant by affecting the concentration of tumor-specific T and B cells.

Stromal cells also express immune-checkpoint protein PDL1, but its mechanism on immunotherapy is still ambiguous In general, T-regulatory Tregs cells are the alternate defense mechanism against autoimmunity, where our immune system fails to eliminate autoreactive T cells without destroying them Surprisingly, Tregs are found in TME, and their survival is promoted by the tumor cells.

Tumors are using Treg populations for their own defense against immune surveillance Likewise, Treg cells can suppress the generation of effector immune cells and produce several immunosuppressant molecules, such as ROS, IL-1, TGFβ, VEGF, prostaglandin E2, adenosine, and galectin 1, and also inhibit antibody production and co-stimulatory molecule expression 37 , The natural population of Tregs originates in the thymus as a defense against autoimmunity, whereas the adaptive Tregs generate during inflammation due to an infection or cancer as a host immunity suppressor Tregs population found in the TME are mostly adaptive but it is not clear yet whether they have differentiated from the natural population or originated from other precursor cells Like Treg cells, tumor cells also form an inflammatory milieu that induces B-regulatory cell Breg population.

Immunosuppressive Breg cells suppress immunopathology and block the production of effector T cells and other pro-inflammatory lymphocytes by producing IL, IL, and TGFβ. By different reports, it has been found that Bregs promote tumor progression by downgrading the production of IFN-γ and IL by Th1 and Th17cells, respectively The high mutagenicity and extreme survival capabilities of cancer cells help them to activate several other immune evasion mechanisms in response to their unstoppable growth Upregulation of the checkpoint receptor ligands against the checkpoints PD1 and CTLA4, which downregulate the proliferation and survival of T cells, is considered a major immune evasion mechanism of cancer cells.

This phenomenon prevents tumor-infiltrating lymphocytes TIL from entering the tumor mass CTLA4, a homolog of CD28, prevents the binding of CDB7 after certain stimulatory signaling to check hyperreactivity. The twist of the story is that tumor cells use the mechanism and block the normal binding of CDB7 and produces negative signaling.

This phenomenon silences the T-cell activation signaling by stopping the IL-2 production and downregulating the cell survival proteins 44 , It regulates T-cell activation by binding to the B7 family ligands PDLs.

PD1:PDLs binding is instigated by the exposure of IFN-γ or tumorigenic signals and generates a negative feedback mechanism to inhibit the immune response. Due to the spontaneous binding of PD1:PDLs, PD1 generates signals to prevent phosphorylation of TCR signaling and inhibits T-cell activation.

It also prevents the production of IFN-γ, TNF-α, and IL-2 and reduces T-cell survival 46 , Turmeric, a common spice obtained from Curcuma longa of the Zingiberacea Ginger plant family, is the natural source of curcuminoids, a mixture of three different components, i.

A major fraction of this compound mixture is curcumin or diferuloylmethane with The crystalline orange-yellow powder is an active polyphenolic phytochemical and has been widely used in medicinal purposes for centuries in India and South Asia, due to its nontoxic but miraculous properties such as anti-oxidant, analgesic, antiseptic, anti-inflammatory, and anti-cancer activity 49 , Curcumin as an immunomodulator interacts not just with various cellular components, such as DCs, macrophages, natural killer cells, and both B and T lymphocytes, but also with modulatory molecules involved in the processes of inflammation and cell proliferation with their downstream signaling In recent times, curcumin has gained the potential therapeutic interest to cure neoplastic disease, because of its significance as an anti-inflammatory and anti-proliferative substance.

The anti-cancer properties of curcumin also modulate several other signaling pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, angiogenesis, and metastasis It increases Th1-type immune responses and upregulates IFN-γ mRNA expression Curcumin effectively reduces Treg cell population and levels of IL and TGFβ.

It also can reduce the expression of CTLA4 and FOXP3 both at protein and mRNA levels Hence, it is considered very interesting to envision the role of curcumin concerning cancer immunotherapies as an immunomodulator Figure 3.

Figure 3 Immunomodulatory and anti-cancer properties of curcumin: It reduces metastasis, angiogenesis, inflammation, and uncontrolled replication by interfering all responsible pathways. On the other hand, it upregulates apoptotic functions by stimulating pro-apoptotic molecules and enhances the function of growth suppressor proteins.

On T cell: Curcumin has the potentiality to modulate the proliferation and activation of T cells. Depending on the dose, it can both suppress and induce the proliferation of T cells.

Several studies reported that curcumin downregulates the proliferation of T cells induced by concanavalin A Con A , phytohemagglutinin PHA , and phorbolmyristateacetate PMA Tomita et al. reported that curcumin can suppress the proliferation of HTLVinfected T cells and primary ATL cells through cell cycle arrest and induction of apoptosis Research carried out by Hussain et al.

stated that in T cell acute lymphoblastic leukemia, curcumin blocks constitutively activated targets of PI3-kinase AKT, FOXO, and GSK3 in T cells, which lead to the inhibition of proliferation and induction of caspase-dependent apoptosis On B cell: Curcumin prohibits the proliferation of B-cell lymphoma cells via downregulation of c-MYC, BCL-XL, and NFκB activities It also blocks Epstein—Barr virus EBV -induced immortalization of B-cells On macrophage: Curcumin modulates macrophage activities, prevents generation of ROS in macrophages, and stimulates enhanced phagocytosis of peritoneal macrophages in mice On Natural Killer cell: Curcumin works against natural killer T cell lymphoma cell lines, where it induces apoptosis by controlling the NFκB pathway and suppression of BCLXL, Cyclin D1, etc.

On DC: Curcumin can reduce the expression of CD80, CD86, and class-II antigens by DCs. Curcumin suppresses the release of inflammatory cytokines like IL-1β, IL-6, and TNF-α from LPS-stimulated DCs.

Curcumin also modulates phosphorylation of MAPK and nuclear translocation of NFκB in DCs It has been observed that chronic inflammation is responsible for several diseases, such as tumor progression, autoimmunity, allergies, and arthritic syndromes. The anti-inflammatory activity of curcumin mainly depends on its potentiality to inhibit NF-kβ activation.

Curcumin inhibits inflammation by downregulating cytokines, IL-1, IL-8, and TNF-α. Curcumin blocks TNF-mediated NF-кB activation in human myeloid ML-1a cells by suppressing activator proteins.

Curcumin also blocks NF-кB activation by hydrogen peroxide and phorbol esters. IL-1β-mediated ICAM-1 and IL-8 gene expression are also inhibited by curcumin, which finally leads to the inhibition of NF-кB activation 65 , It transduces signal type 1 and 2 cytokine receptors in response to pro-inflammatory cytokines.

Curcumin has a distinct role in the inflammatory MAPK pathway. Curcumin significantly lowers the PGE2 prostaglandin E2 level and the expression of TNF-α and IL-6 by preventing phosphorylation and activation of p38 MAPK functioning Kim et al.

Curcumin acts upon numerous cell proliferation signaling pathways that are intensely associated with cancer progression. Curcumin inhibits NF-кB signaling by suppressing IкB kinase activity. Cyclin D1, the proto-oncogene that is highly expressed in several types of cancer and acts in cell cycle progression and proliferation, is also suppressed by curcumin Along with this, curcumin also inhibits excessive TGFβ receptor signaling and EGF- and EGFR-mediated signaling pathway and remarkably controls epithelial-to-mesenchymal transition, metastasis, and tumor progression, respectively A significant activity of the telomerase enzyme has been observed in cancer cells, which prevents telomere shortening and stimulates continuous cell proliferation signaling.

Curcumin prevents human telomerase hTERT activities and reduces hTERT-mRNA expression that led to telomere shortening. By targeting telomerase activities, controlling replicative cell senescence and mortality, curcumin ultimately controls the uncontrolled cell proliferation of cancer cells Numerous studies have reported the incredible potentiality of curcumin to inhibit cell migration, invasion, and colony formation in vitro and decrease tumor growth and metastasis in vivo.

Curcumin downgrades the expression of matrix metalloprotease, CCRX4, COX2, ELAM1, and ECAM1, which are essential for metastasis Besides, curcumin also hampers the functioning of SLUG, SNAIL, FAK, TWIST, and other essential transcription factors that play a crucial role in the metastasis process Several studies have reported that curcumin upregulates the expression of p53, which was suppressed by cancer cells and enhances apoptosis Curcumin blocks the phosphorylation of another tumor suppressor protein, RB Retinoblastoma , which plays a significant role in the cell cycle process Curcumin induces both TPdependent and -independent apoptosis of cancer cells by upregulating pro-apoptotic molecules such as BAX, BIM, and PUMA and by downregulating anti-apoptotic molecules like BCL2, BCL-XL, and Survivin.

Consequently, the caspase activity gets enhanced and proceeds to apoptosis Besides, curcumin stimulates lysosomal proteases, phosphatases, and lipase activities, which induce autophagy-mediated cell death Blocking the angiogenesis process is a vital step to control tumor outgrowth.

Immunotherapy is developed depending on seven basic steps, i. Based on these cellular and molecular mechanisms, different types of immunotherapies were designed to boost the immune system. Necessary modulation of the regulatory mechanisms has been incorporated with these steps to improve the quality and quantity of the anti-tumor immune responses.

There are two categories of cancer immunotherapy: active and passive. Sometimes, these two are combined as an additional option. In the case of active therapy, the host immune system directly attacks the TAAs on the tumor surface, which could be specific proteins or carbohydrates expressed especially in tumor cells with the administrating agents such as mAbs, cytokines, or lymphocytes.

On the other hand, passive immunotherapy enhances the basic anticancer response by boosting host immunity This tries to activate the self-immune system for attacking tumor cells through vaccination, nonspecific immunomodulation, or targeting certain antigen receptors.

However, the number of responders and non-responders varies widely with the same malignancy after the same immunotherapeutic treatment The inability of immunotherapy to eliminate grown tumors completely is a constant challenge.

The numerous cunning suppressive mechanisms of cancer cells and some restrictions of the ongoing immunotherapies are counts as the reasoning behind the failure or wavering responses As stated before, tumor growth is associated with the escape of immunosurveillance processes and causes general immunosuppression in the body.

Due to the restoration of the Th1 immune response, curcumin is also able to upregulate IFN-γ mRNA expression and promotes cancer regression Bhattacharyya et al.

showed that curcumin can effectively reduce Treg population and levels of IL and TGFß 7. In the next part, we will discuss the conventional immunotherapies that are applied against tumor immune evasion and the role of curcumin as an immune modulator to recreate tumor immune surveillance from tumor immune escape Figure 4 , created by BioRender.

Progression of tumor is associated with Treg cell population augmentation in the TME and correlates with poor prognosis of cancer It not only secretes immunosuppressive cytokines like TGFβ and IL but also expresses high-affinity IL-2 receptor CD25, which sequesters IL-2 from the tumor milieu.

Subsequently, it leads to the effector T-cell apoptosis In the scenario, Tregs are a good target for immunotherapy in cancer patients The goal of this therapy is to downregulate the Treg population to increase the level of IL-2 and increase the survivability of effector T cells as well.

Denileukin Diftitox, a recombinant drug combining IL-2 and diphtheria toxin, has been frequently used for leukemia therapy and also for another carcinoma. Despite this, failure has been observed with cancer-induced antigen-specific Tregs Another important issue is why the number of Tregs is increased in cancer patients.

Some questions arise: Are the cells trying to suppress anti-tumor immunity recognized as an auto-reactive immune response?

Are they reacting to the inflammation? Is there some other issue? These unanswered questions make the therapy difficult and bring forth additional confusion, such as which local factor in the TME acts as a catalyst for Tregs, what is the precursor population of Tregs, what is antigen specificity of Tregs, and how it is affecting effector immune cells.

Practical practice in therapeutic background highlighted the fact that the agents used to reduce Tregs function can work correspondingly well or not in all kinds of mediums, such as blood, tumor, and draining lymph nodes.

The relationship between Treg depletion in the blood and at local sites is still ambiguous, and whether such observations are effective to predict immunologic or clinical outcomes remains unknown In context to overcome these ambiguities, several studies have indicated that curcumin could target Treg cells and convert them into Th1 cells, which possess anti-tumor effects.

The results showed that after 2 weeks of treatment with curcumin, the number of peripheral Treg cells distinctly declined while the number of peripheral Th1 cells was improved.

It has been assumed that curcumin enhanced the conversion of Treg cells to Th1 cells by suppressing the expression of Foxp3 and inducing the expression of IFN-γ On this ground, it is evident that curcumin has the potentiality in suppressing the activity of Treg cells, and due to its significant role, it may be possible to use curcumin as an immunotherapy modulator for Treg-mediated therapy in the future.

The Food and Drug Administration FDA has approved significant numbers of mAbs to treat solid and hematological malignancies and more novel mAbs are under clinical trials Presently, several types of mAbs have been registered, such as conjugated, bi-specific, and naked mAbs that are applied to treat cancers Conjugated mAbs can be linked to a chemotherapy agent or a radioactive particle, which can carry these materials instantly to the tumor cell Brentuximab vedotin, a chemo-labeled conjugate mAb, is targeting CD30 antigen that presents on lymphocytes, used for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma 96 , Similarly, a radio-labeled antibody has a radio-active particle attached to it Bispecific mAbs consist of two various parts of mAbs, e.

The most common form of mAbs is naked mAbs, which is highly used to treat cancer. However, the clinical success rate of this therapy is still not satisfactory. The prime reason is the lack of specificity of the tumor neo-antigens that can be targeted by mAbs.

TAAs are not a specific tumor neo-antigen, rather they are tissue differentiation antigens, which correspondingly expressed in certain normal healthy cells. Additionally, frequent genetic mutations during tumor development generate secondary neo-antigens, which unfortunately escape from primary recognition, as CTLs are only able to identify the primary neo-antigens expressed on HLA class I molecules So, the specificity between CTLs and TAA is a major barrier for this therapy.

In some conditions, the developed malignant cells and TME turn off the expressed TAAs through the process of immune tolerance induction and inhibits anti-tumor response, respectively 9.

Accordingly, some common side effects, such as low blood pressure, headache, fever, nausea, chill, weakness, and diarrhea, have been recorded, along with several serious health issues, which might be lethal in some cases Last but not the least, the production cost of this therapy is very high.

Though individually this therapy is not found very encouraging, when curcumin is linked with the cleavable arm to a mAb, its functional efficacy has been increased up to fold more in eliminating murine melanoma B16F10 cell-induced brain tumor.

So, such a novel applicable strategy of converting curcumin into a potent anticancer immunomodulatory agent may provide a mechanistic framework for its action Cancer vaccine is the immune modifier, which acts via stimulation or re-establishment of the immune system competence to combat cancers It is similar to monoclonal antibody therapy, which involves conventional vaccination methods to induce an immune response.

Whole cancer cells or a particular protein or peptide are used to trigger the immune system Two general types of vaccines are mainly applied, i. Preventive vaccines work depending on the antigens taken by infectious factors so that detection of them by the immune system can be easy It activates the immune system with the targeted T cells for eliminating target tumor cells.

The FDA-approved hepatitis B virus HBV vaccine and human papilloma virus HPV vaccine are such kinds of vaccines Besides, its capacity to invade other tumor-specific antigens as well develops immune responses equally 5.

However, the main reason for the differences in patient response rate is the antigen specificity of the vaccine as the vaccine is designed based on the peptide antigen complexes with HLA present on tumor cells Thus, designing a commercial form of the vaccine is very much patient- and tumor type-specific and needs to be administrated to a minimal subset of the patient that expresses the same antigen.

Even though the main reason for its failure is lack of specificity, it is really hard to commercialize a standard tumor antigen. Thus, necessary immunomodulation has been considered as a remedy. With an intention to study the immunomodulatory effects of curcumin in cancer treatment, curcumin—polyethylene glycol PEG conjugate, an amphiphilic curcumin-based micelle, has been used in combination with conventional vaccine therapy in an advanced melanoma model.

This combination resulted in a synergic anti-tumor effect and a depletion in the levels of immunosuppressive factors, such as myeloid-derived suppressor cells and Treg cells. Hence, it can be suggested that derivatives of curcumin conjugate may be used as a potential modulator to promote cancer vaccination not only in advanced melanoma cases but also for other carcinomas One of the most common forms of immunotherapy for hematological and solid malignancies is the ACT of TAA-specific T cells Previous researches on the ACTs are based on the use of TILs, though this strategy has been constrained due to the problems for expansion of viable TILs and restricted exhibition of certain effector functions Hence, for resolving the problems, applications based on chimeric antigen receptor CAR and TCR-engineered T cells have been developed that act via genetic modification and increase the therapeutic efficiency One of the conventional therapies for metastasis melanoma is to transfer antigen-specific TCR genes into lymphocytes by transducing T cells with retroviruses or lentiviruses to ensure the expression of TCRs.

This has been applied to target certain TAA and eliminate tumor cells Although, in metastatic melanoma patients, the outcomes seem very promising, in general, TCR technology has been found less fascinating, as it is MHC-restricted CAR-modified T cells are the second group of the engineered T cells, applied to enhance the specificity and anti-tumor capacity 9.

In comparison with TCRs, CAR-T cells exhibit antibody-like specifications that could detect MHC-non-restricted structures on the target cell surfaces and subsequently recognize tumor cells in an MHC-un-restricted mode However, this is the main disadvantage of its application.

Since there are only a few tumor-specific cell surface antigens, it restricted the specificity of CAR-T cells and narrowed the application In addition, acute cytokine release syndrome CRS , as a result of the supraphysiologic level of cytokine production upon antigen recognition, is a common side effect of this therapy.

These drawbacks limited its use as a therapeutic option for both solid and hematological tumors , Very little is known about the effect of curcumin when it is combined with T-cell-based therapy, such as ACT or CAR T cells both in in vitro and in vivo models.

Chang et al. G7 tumor cells along with the inhibition of TGFß. This research suggested that the multi-targeting benefit and immunomodulation of curcumin may condense the efficiency of adoptive T-cell therapy in combination treatment Immune checkpoints are essential for host immune backup to prevent autoimmunity.

It has been observed that cancer cells use this mechanism to escape from the host immunity system by deactivating TILs, concerning the activation of T cells. Immune checkpoint blockers are developed with the aim of increasing immune responses against cancer T-cell surface molecules, CTLA4, PD1, T-cell immunoglobulin and mucin domain 3 Tim-3 , and lymphocyte activation gene 3 LAG3 are some essential checkpoint modulators Tumor expression of these markers would lead to enervation of the immune system Thus, the above molecules become the center of attention by researchers as the target PD1 and CTLA4 are the two most common checkpoints clinically targeted for treatment.

Immune checkpoint inhibitors are mainly the types of mAbs that block immune checkpoint receptors and allow activated T cells to clear tumor cells 9. PD1 or CTLA4 blocking results in deactivation of Tregs and other immunosuppressive mechanisms and consequently activated anti-tumor T cells for defense In recent times, nearly clinical trials are ongoing for testing the efficiency and safety of ICB in different types of cancers Although this therapeutic approach is found to be very effective, a varying response rate with some side effects has been observed among patient cohorts with the same cancer type Specific consequences such as hepatic, gastrointestinal, endocrine, dermatologic, and other less prevalent inflammatory syndromes are highly associated with checkpoint inhibition.

Anti-PD1 therapy needs more research on TME to identify the exact mechanism of its upregulation there Clinically, it has been observed that anti-CTLA4 or anti-PD1 mAbs induce autoimmune reactions.

Hence, the question arises regarding its control over auto-reactive T cells, and this insufficient understanding of the mechanism restricted its use as a single-agent therapy , The role of curcumin on immune checkpoints is not clear yet and requires more researches.

In parallel, some basic anti-tumor functioning of curcumin such as ICB therapy assumes to be effective. CTLA4 is one of the key transcription factors, involved in the regulation of the Treg transcriptional program and is vital for Treg development and functioning The study has shown that curcumin can reduce the expression of CTLA4 both at protein and mRNA levels Curcumin is also effective in reducing the number of Treg cells, which further reduces the number of CTLA4 consecutively.

Numerous studies have reported that curcumin has the potentiality to convert Treg cells into Th1 cells, which possess anti-tumor effects Another study reported the effect of curcumin on immune suppression in tongue squamous cell carcinoma. Curcumin treatment inhibited the expression of the PDL1 both in vivo and in vitro , which sequentially blocked the binding with PD1 and promote anti-tumor T-cell proliferation Hence, curcumin has been shown to modulate the expression of CTLA4 and PDL1 and application of curcumin together with immune checkpoint blockers may establish a better approach to eradicate tumor cells.

DCs are very distinct and potential antigen-presenting cells. It represents TAAs effectively to generate tumor-specific immunity. Numerous animal studies have confirmed that DCs can stimulate T cell-mediated tumor elimination when loaded ex vivo with tumor antigens.

These observations have prompted inspecting the immunological and clinical effects of antigen-loaded DCs directed as a therapeutic vaccine to cancer patients.

The outcomes from these clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer advocate these immunotherapeutic strategies that would be beneficial with the antigen-presenting properties of DCs and might be proven as efficient and widely applicable to human tumors Irrespective of these parameters, it has been observed that STAT3 activation in DCs and Tregs in TME involves the suppression of the anti-tumor immune responses.

Various cytokines, such as IL-6 and IL-8, play immune-suppressive roles by inhibiting DC function and alternatively by uprising MDSCs and Tregs It has been observed that curcumin basically inhibits the immune-stimulatory function of DCs and interferes in myeloid DC maturation reported that curcumin downregulates the production of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, from maturing DCs, and it has been observed that curcumin-treated DCs exhibited suppression of Th1 responses, confirming the inhibitory effect of curcumin on DCs maturation In spite of that, recent studies have reported that in some cases, curcumin indirectly helps DCs to generate tumor-specific immune responses.

Curcumin enhances anti-tumor T-cell responses by inhibiting STAT3-activated inflammatory signaling in TME and also in DCs, which reestablishes the anti-tumor response again. It has been demonstrated that curcumin indirectly restores the functioning of DCs by reducing IL-6 and IL-8 productions by cancer cells via STAT3 inhibition So, the use of curcumin as an additional modulator with DC-based immunotherapy could be a wise thought but it still requires more research to understand the mechanism.

In order to offer a rational model for achieving optimum efficiency, it is highly essential to understand properly the particular mechanism of the parent medicine and adjuvant combinations Combinatorial impacts have been obtained by combining two specific partner medicines with lesser, equivalent, and or greater impact.

Such impacts might be antagonistic, potentiation, and synergistic If the obtained impact is better than the whole impact of the medicines without cross-reactions and several functioning targets or paths, it will be considered as a synergistic combinatorial impact In case the impact is higher than or equivalent to the whole impact of individual medicines with some distinct targets or pathways, it will be the additive impact.

When the activity or impact of one medicine can be seen by the other, it would be potentiation impact , Curcumin has multiple potentials due to its numerous antineoplastic mechanisms for cancer therapy.

Curcumin, a chemo-sensitizing agent, also enhances the efficacy of several chemotherapeutic agents When curcumin is combined with bevacizumab therapy, it suppressed tumor growth significantly with no physical side effects This highly indicates the therapeutic promise of adjuvant application of curcumin for treating cancer, particularly combined with several mAbs A clinical trial has been executed by Basak et al.

with oral cancer patients where APG, a botanical drug containing multiple polyphenols, including curcumin has been administrated orally.

According to the study, APG was absorbed well and significant trace of curcumin has been found in the blood and in tumor tissues. This trial reported the downregulation of inflammatory markers and Bacteroides species in the saliva and upregulation of the immune T cells in the tumor tissue.

Additionally, it reduced inflammation and attracted cytotoxic T cells to the tumor site, signifying its potential usage in combination with immunotherapy drugs Though curcumin has been utilized as a promising agent for chemoprevention and cancer immunotherapy, it is not considered as a cure for everything from a clinical perspective.

Since curcumin has poor aqueous solubility, i. It is hydrolyzed fast and only soluble in acidic conditions After intravenous or intraperitoneal administration, a significant amount of curcumin is excreted via bile in the form of hexahydrocurcumin and tetrahydrocurcumin glucuronide derivatives The poor bioavailability of oral curcumin in the GI tract restricts its potentiality against cancer immunosuppression Even after the oral daily intake of mg or higher doses of curcumin in patients with advanced colorectal cancer, the detected concentration of curcumin in peripheral and portal blood was in nanomolar levels It has been assumed that the main reasons for such poor bioavailability are its poor absorption, rapid metabolism, chemical instability, and rapid systemic elimination.

Along with poor aqueous solubility and low bioavailability problem, several other therapeutic issues have emerged over time such as lack of dose—response proportionality, uncontrolled precipitation, use of excessive co-solvents, and requirement of safe medium to solubilize basic or acidic , which impedes its effectiveness as a chemotherapeutic drug against cancer Thus, the development of an appropriate strategy to upgrade the bioavailability and solubility of curcumin is a vital concern for a beneficial therapeutic approach against immunosuppression induced by tumors.

To overcome these limitations, nanotechnology-based drug delivery systems have been established as a reliable and promising approach. Nanotechnology-based drug delivery systems of curcumin not only improve poor bioavailability but also enhance biological activities and selectively target cancer cells.

This technology packs the active pharmaceutical ingredient of curcumin into nano-sized particles, ranging from 10 to nm to enhance systemic bioavailability. It also enhances the dissolution rate of curcumin and appears as an applicable method to deliver insoluble drugs It is a solubilizing and stabilizing agent that can solubilize the curcumin in a lipophilic cavity.

The outer hydrophilic surface contributes in greater dispersion of the formulation; Dendrimer or dimers : It is a core—shell nanostructure, synthesized in a layer-by-layer fashion where several pharmaceutical active compounds are directly connected by stable chemical bonding; and Solid lipid nanoparticles SLNs : SLNs are an aspherical lipid core matrix that can solubilize curcumin and the lipid core is stabilized through emulsifiers 49 , , The encapsulation of curcumin into the exosomes, the extracellular secretary nano-vesicles, also enhances its stability, solubility, and bioavailability Furthermore, several bio-enhancers are also available such as piperine, quercetin, and silibinin, which prevent or reduce the metabolism of curcumin, and it has been expected that application of these bio-enhancers with curcumin as dual drug-loaded nanoparticles will be advantageous Recently, pure curcumin nanoparticles without any carrier conjugates have been developed, which have 50 times more effectiveness and better bioavailability than normal curcumin and have shown the potentiality to suppress markers of Treg cells and recover immune responses in experimental models.

They are developed by dissolving pure curcumin in ethanol and homogenization at high pressure with water containing 0.

Figure 5 Curcumin nano formulations: 1 Liposomes, 2 Polymeric micelles, 3 Polymer nanoparticles, 4 Nanogels, 5 Nanoemulsion, 6 Solid lipid nanoparticles, 7 Inclusion complex, 8 Dendrimer, 9 Phytosome, and 10 Curcumin nanoparticles.

Even though nanotechnology-based drug delivery has a promising future towards effective cancer therapy, there are still certain limitations. Complications regarding drug targeting and loading capacity, in vivo fate of the carrier—molecule conjugates, toxic effects of the carrier molecule, its large-scale production, stability during long-term storage, and overall production costs are challenging to deal with.

Specifically, the toxic effects of nano-formulations in the body are definitely an emergent concern. Even after the toxicity and biocompatibility of the carrier materials are tested, the properties of the nanoparticles still differ frequently.

Hence, before approval for a clinical trial, thorough evaluations are extremely required to determine the toxicity of the carrier materials and their metabolites The violation of cancer is one of the leading causes of death worldwide and it is still a challenge to find out some promising therapeutic approaches against the rioter tumor cells.

The soldiers of the immune system play major roles in eradicating tumor cells. Hence, boosting up the soldiers with biotechnology and genetic engineering is considered as an advantageous development to fight cancer cells and also develop novel immunotherapies.

Despite its immense success rate, some weaknesses are still haunted by its maximum success, which has been already discussed above. Studies continue to reveal its potentiality to interact with the immune system, emerging as an important booster due to its anti-cancer properties.

Since immunotherapies have been developed to eliminate tumor cells overruling their escape mechanisms, curcumin can be used as a potent immunomodulator or booster backup. Even though several reports have submitted the general immunosuppressive role of curcumin and its low bioavailability in circulation, numerous studies report that curcumin increases anti-tumor immunity through various modes, as discussed in this review.

Therefore, modifications of the conventional immunotherapies seem to be an important strategy by which curcumin counteracts cancer development. This further proclaims its effectiveness as an anti-cancer agent and points out the need to use it as an adjuvant immunotherapeutic agent.

This leads to the development of nano-based strategies for appropriate delivery and increased bioavailability of curcumin, which may finally lead to its use as a proper immunotherapeutic modulator. SP undertook the background literature study and prepared the initial draft of the manuscript and the figures.

GS supervised the entire project and made final corrections to the draft. All authors contributed to the article and approved the submitted version.

This work was supported by research grants from the Department of Biotechnology, Government of India. GS is a National Academy of Science India Platinum Jubilee Senior Scientist. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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The turmeric is a natural, anti-inflammatory to quell the swelling of sinuses, and black pepper helps move the turmeric through the bloodstream to where it needs to go. Ginger and Turmeric Hot Cider Warm apple cider is the perfect winter comfort drink for Lori Bumbaco, Oncology Dietitian at NorthShore.

This special cider combines ginger and turmeric for a unique flavor and nutrition profile. Nutritional information per serving : Calories: Total Fat: 0 g Carbs: 30 g Protein: 0 g Dietary Fiber: 0 g Sodium: 8 mg. Recipe original appeared in the American Institute for Cancer Research.

Warm Spiced Turmeric Milk Another good way to get a healthy dose of turmeric during cold winter months is by substituting hot chocolate for this drink from Emmaline Rasmussen, MS, RD, LDN, Clinical Research Dietitian at NorthShore.

Home » Healthy You » 3 Turmeric Remedies to Boost Immune System. By: Lauren McRae Turmeric is being studied for it's anti-inflammatory and antioxidant properties. of Honey For allergies and colds, Leslie Mendoza Temple, MD, ABOIM , Medical Director, NorthShore Integrative Medicine Program, suggests this turmeric concoction: Ingredients: Combine all of these ingredients into 1 tsp.

of raw local honey, then eat the honey. A pinch of turmeric A pinch of black pepper A pinch of ginger Dr. Ingredients: 1 cup fresh, sweet apple cider 1 tsp grated fresh ginger 1 tsp grated fresh turmeric 1½-inch by ½ -inch strip lemon peel, white part included Directions: In a small saucepan, combine cider, ginger, turmeric and lemon peel over medium-high heat.

Heat until a ring of bubbles appears around the edge of the pan — about 3 minutes. Cover pan and set aside to steep for 5 minutes. This review analyses the relationships between immunodeficiency and the onset of infectious diseases and discusses the effects of curcumin and its derivatives on the immune response.

In addition, we analyse some of the preclinical and clinical studies that support its possible use in prophylaxis or in the treatment of infectious diseases.

Lastly, we examine how nanotechnologies can enhance the clinical use of curcumin. Keywords: B cells; T cells; bacterial infections; curcumin; inflammatory immune response; primary immunodeficiency; secondary immunodeficiency; sepsis; viral infections.

Abstract Primary and secondary immunodeficiencies cause an alteration in the immune response which can increase the rate of infectious diseases and worsened prognoses.

Publication types Review. Substances Curcumin Cytokines.