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Radiotherapy and chemotherapy are two famous modalities in tumor‐targeted therapy that lead to systemic and local toxicities for normal tissues. Moreover, several studies have confirmed that exposure of the tumor to radiation or chemotherapy drugs stimulate some signaling pathways in the tumor microenvironment (TME), leading to resistance of cancer cells to apoptosis, as well as promoting angiogenesis and tumor growth. Nuclear factor kappa B (NF‐κB) plays a central role in the regulation of inflammatory responses in both normal tissues and tumors via the release of several cytokines, regulation of prostaglandins, reduction/oxidation (redox) reactions, angiogenesis, and cell death. Upregulation of NF‐κB in normal tissues causes an appearance of inflammatory reactions and oxidative stress, whereas it regulates angiogenesis and suppresses apoptosis, leading to resistance to subsequent doses of radiation or chemotherapy. Selective inhibition of NF‐κB in experimental studies has shown promising results for tumor sensitization via apoptosis induction, inhibition of angiogenesis, and increasing delay of tumor growth. The use of some agents for NF‐κB inhibition has been shown to alleviate radiation/chemotherapy toxicities in normal cells/ tissues. In this current review, we explained the pivotal role of NF‐κB in both normal tissue toxicity and tumor resistance. We also discussed the promising strategies for overcoming these problems with regard to chemotherapy and radiotherapy. [ABSTRACT FROM AUTHOR]

CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune‐resistance. Cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8 + T cell‐mediated antitumor immune responses. Thus, CD8 + T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8 + T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4 + T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so‐called infiltrated–inflamed [I–I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8 + T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death‐1 receptor (PD‐1)–ligand (PD‐L1) and CTL‐associated antigen 4 (CTLA‐4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8 + T cells and renewing their priming, respectively, and thereby eliminating antigen‐expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells. Tumors have specific mechanisms to break T cell responses. CD8+ T cells are the key immune cells for killing cancer cells presenting major histocompatibility complex (MHC) class I molecules. For pursuing this purpose, the cells must first be primed by their cardinal interactions with dendritic cells (DCs), natural killer (NK) cells, and CD4 + T cells, among them play essential roles for this priming. Then, the primed cells are activated to form effector cytotoxic T lymphocytes (CTLs) for killing cancer cells via release of granules or induction of FasL‐mediated apoptosis. In the established tumors, however, the function of these key effector cells is suppressed by immunosuppressive cross‐talking between cancer cells with tumor stromal cells like cancer‐associated fibroblasts (CAFs), regulatory T cells (Tregs), and macrophage type 2 (M2) cells. CTL‐based therapy can distract cancer cells, and the density of CD8 + T cells infiltrated to the invasive site of tumor is a predictive marker for influencing the outcomes of immune checkpoint blockade (ICB) blockade therapy. It is suggested to use a combination of immunotherapeutic approaches for rescuing the exhausted CTLs and switching them toward their active effector profile for retaining immunoactivation within the tumor microenvironment (TME) for combatting tumors and enhancing the efficacy of chemo or radiotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are self‐renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor‐type dependent. The transition between CSCs with cancer cells and other non‐CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer‐associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non‐CSCs toward attaining a CSC‐like phenotype. WNT/β‐catenin, transforming growth factor‐β, Hedgehog, and Notch are important signals for maintaining self‐renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non‐CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens. Most of the tumors are occupied with a number of self‐renewing cells called cancer stem cells (CSCs) that are contributed to the initiation, maintenance, and thriving cancer. The cells have rather similar characteristics to other stem cells located in the niche of body organs, but they have not essentially the same responses to the diverse stimuli. There is evidence for repopulation of CSCs after treatment with chemo/radiotherapy, which is possibly because of their highly plastic feature. Normal stem cells have the proclivity to transform into CSCs when they undergo continuous mutagenesis or receive tumorigenic signals of the tumor microenvironment (TME). Upon this transition, CSCs receive markers from their progeny. The rate of expression of these markers in CSCs is dependent on the type of tumor. CSCs can differentiate into cancer cells. In turn, cancer cells can dedifferentiate toward attaining a CSC‐like phenotype. Cancer‐associated fibroblasts provide a supportive niche for CSCs and release external cues for regulating cancer cell stemness. An effective therapeutic strategy is to target both CSCs and non‐CSCs to preclude a possible chance of tumor recurrence. Making a control over tumorigenic clues from TME or controlling intrinsic CSC signaling are optimistic approaches to break down CSC‐related tumorigenesis. Shifting CSCs from self‐renewal to differentiation can also be therapeutic through limiting their proliferative capacity, tumor recurrence, metastasis, and resistance. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) represent a low number of T‐cell population under normal conditions, and they play key roles for maintaining immune system in homeostasis. The number of these cells is extensively increased in nearly all cancers, which is for dampening responses from immune system against cancer cells, metastasis, tumor recurrence, and treatment resistance. The interesting point is that apoptotic Tregs are stronger than their live counterparts for suppressing responses from immune system. Tregs within the tumor microenvironment have extensive positive cross‐talks with other immunosuppressive cells including cancer‐associated fibroblasts, cancer cells, macrophage type 2 cells, and myeloid‐derived suppressor cells, and they have negative interactions with immunostimulatory cells including cytotoxic T lymphocytes (CTL) and natural killer cells. A wide variety of markers are expressed in Tregs, among them forkhead box P3 (FOXP3) is the most specific marker and the master regulator of these cells. Multiple signals are activated by Tregs including transforming growth factor‐β, signal transducer and activator of transcription, and mTORC1. Treg reprogramming from an immunosuppressive to immunostimulatory proinflammatory phenotype is critical for increasing the efficacy of immunotherapy. This would be applicable through selective suppression of tumor‐bearing receptors in Tregs, including FOXP3, programmed death‐1, T‐cell immunoglobulin mucin‐3, and CTL‐associated antigen‐4, among others. Intratumoral Tregs can also be targeted by increasing the ratio for CTL/Treg. Regulatory T cells (Tregs) are essential mediators of immunosuppression in established tumors. Tregs express a wide range of receptors and markers for this purpose, and they have extensive cross‐talks with almost all immunosuppressive cells of tumor stroma, including cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, cancer cells, and myeloid‐derived suppressor cells (MDSCs). Treg cell‐mediated immunosuppression is more vigorous when the cells are committed to apoptosis after high exposure of the cells to the reactive oxygen species (ROS) within the tumor microenvironment (TME). Tregs can be transformed to their immunostimulatory phenotype by targeting their relative markers. This transformation is considered as a promising approach for immunotherapy of cancer. For having optimistic outcomes in targeting cancer, immunotherapy is needed to be used in combination with appropriate chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)‐β is a multitasking cytokine such that its aberrant expression is related to cancer progression and metastasis. TGF‐β is produced by a variety of cells within the tumor microenvironment (TME), and it is responsible for regulation of the activity of cells within this milieu. TGF‐β is a main inducer of epithelial–mesenchymal transition (EMT), immune evasion, and metastasis during cancer progression. TGF‐β exerts most of its functions by acting on TβRI and TβRII receptors in canonical (Smad‐dependent) or noncanonical (Smad‐independent) pathways. Members of mitogen‐activated protein kinase, phosphatidylinositol 3‐kinase/protein kinase B, and nuclear factor κβ are involved in the non‐Smad TGF‐β pathway. TGF‐β acts by complex signaling, and deletion in one of the effectors in this pathway may influence the outcome in a diverse way by taking even an antitumor role. The stage and the type of tumor (contextual cues from cancer cells and/or the TME) and the concentration of TGF‐β are other important factors determining the fate of cancer (progression or repression). There are a number of ways for targeting TGF‐β signaling in cancer, among them the special focus is on TβRII suppression. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor. These complex interactions require more sophisticated approaches for cancer therapy, and, therefore, advancing knowledge about dominant drivers of cancer within the TME is critical for designing therapeutic schemes. This review will provide knowledge about TME architecture, multiple signaling, and cross communications between cells within this milieu, and its targeting for immunotherapy of cancer. Cross‐talks between various cells in the stroma of tumor microenvironment (TME) in favor of or against of tumor progression. Release of a variety of proteins, transcription factors, cytokines, chemokines, and so forth from cells inside the TME direct the fate of cancer. Concentration of these TME components along with temperature, circadian rhythm, and pH inside this microenvironment determine the fate of signaling. Complexity of the TME is a reason for failure of most of the conventional therapies against cancer. [ABSTRACT FROM AUTHOR]

Cyclooxygenase‐2 (COX‐2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo‐ and radiotherapy. COX‐2 is released by cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX‐2 induces cancer stem cell (CSC)‐like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX‐2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX‐2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX‐2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX‐2 on cancer cells or its regulation. Members of mitogen‐activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor‐κβ are main upstream modulators for COX‐2 in cancer cells. COX‐2 also has interactions with a number of hormones within the body. Inhibition of COX‐2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX‐2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX‐2 inhibition also sensitizes cancer cells to treatments like radio‐ and chemotherapy. Chemotherapeutic agents adversely induce COX‐2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX‐2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer. Cyclooxygenase‐2 (COX‐2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo‐ and radiotherapy. COX‐2 is released by cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX‐2 induces cancer stem cell (CSC)‐like activity and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most prevalent cancer in the world. There are many risk factors involved in CRC. According to recent findings, the tumor microenvironment and feces samples of patients with CRC are enriched by Fusobacterium nucleatum. Thus, F. nucleatum is proposed as one of the risk factors in the initiation and progression of CRC. The most important mechanisms of Fusobacterium nucleatum involved in CRC carcinogenesis are immune modulation (such as increasing myeloid‐derived suppressor cells and inhibitory receptors of natural killer cells), virulence factors (such as FadA and Fap2), microRNAs (such as miR‐21), and bacteria metabolism. The aim of this review was to evaluate the mechanisms underlying the action of F. nucleatum in CRC. One of the probabilities in colorectal cancer (CRC) development is Fusobacterium. F. nucleatum could contribute in CRC development through virulence factors, microRNAs (miRNA), immune evasion, and increasing metastasis. [ABSTRACT FROM AUTHOR]