Targeting the V-Type Immunoglobulin Domain-Containing Suppressor to T Cell Activation (VISTA) with Agonist Monoclonal Antibodies in Autoimmunity.

The recognition of self-antigens by the T-cell immune system can results in autoimmunity. Current treatments of autoimmunity include non-steroid anti-inflammatory drugs and treatments aimed to control the immune system directly. Additionally, inhibiting signaling pathways that encourage T cell activation are promising strategies to help increase self-tolerance and control the inflammatory immune response. Despite the many treatments available, there are still great risks that accompanies each therapy; therefore, the shift towards immune checkpoint therapy is promising as it specifically targets the activated autoimmune T cells. In contrast to cancer, immune check point inhibitors (ICIs) for autoimmune treatment are attractive targets for the amplification of inhibitory functions of autoimmune T cells. A particular protein of interest for autoimmune therapy is the immune checkpoint protein V-type immunoglobin domain-containing suppressor of T cell activation (VISTA) or programmed dealth-1 homolog (PD-1H) of the B7 family. VISTA acts as both a ligand [on antigen presenting cells (APCs) and other cells] and as a receptor (on T cells). It functions as an immuno-suppressor by decreasing T cell proliferation, balancing the T cell/T regulatory cells (Tregs) ratio, and inhibiting cytokine production and inflammation. For the treatment of autoimmunity, an agonist anti-VISTA mAb is needed to interact and activate the inhibitory intracellular signaling pathways that result in the inactivation of the autoimmune T cells. New developments such as VISTA.cartilage oligomeric matrix protein (VISTA.COMP) and anti-human VISTA (anti-hVISTA) mAbs 7E12 and 7GF are potential drug candidates to help downregulate autoimmune responses and reduce the inflammatory states of patients with autoimmunity.

Long non-coding RNAs (lncRNAs) signaling in cancer chemoresistance: From prediction to druggability.

The acquisition of cancer cell resistance to conventional chemotherapeutics is considered the major driver of treatment failure and disease recurrence in most solid and hematological malignancies. The molecular basis of tumor chemoresistance has been extensively investigated and newly identified gene signatures have eventually paved the way towards the development of novel therapeutic interventions in the era of precision medicine in oncology. Long non-coding RNAs (lncRNAs) are defined as a class of transcripts longer than 200 nucleotides that lack translational activities and are highly abundant across the human genome. LncRNAs show higher tissue and cell subtype specificities than most mRNAs, while their biological relevance has been associated with the regulation of coding gene expression at the epigenetic, transcriptional, and post-transcriptional levels, regulation of DNA replication timing and chromosome stability, as well as aging and disease. Given their specific expression and functional diversities in a variety of human cancers, lncRNAs have currently received extensive attention regarding their implications in the disease pathophysiology and their potential applications as diagnostic/prognostic biomarkers and/or therapeutic targets in cancer. Over the last decade, different lncRNAs were found to play pivotal regulatory roles in drug resistance of certain cancer cell types via mechanisms that include among others, alterations in drug efflux, metabolism and targeting, cell death machinery, DNA damage repair, epithelial to mesenchymal transition (EMT), autophagy and oxidative stress management, as well as modifications in epigenetic regulators, oncogenes, and miRNAs. The present review discusses the current state of knowledge on the emerging research into lncRNAs as drug resistance regulators and predictors in various tumors, emphasizing lncRNA patterns associated with cancer stemness, certain drug classes and common underlying mechanisms of action. The review further reveals cutting edge strategies for lncRNA modulation and the current progress on lncRNA-targeting molecules designed to overcome cancer resistance. Our input is a reference for future research investigations on cancer chemosensitivity and provides new insights into the clinical development of lncRNA-targeted pharmacological interventions.

Defective Natural Killer Cells in Melanoma: Role of NKG2D in Pathogenesis and Immunotherapy.

Melanoma is the most aggressive and deadliest form of skin cancer, and its prognosis is very poor. Although the early detection is responsive to many treatments, metastatic melanoma is refractory to most of them. In the United States, skin melanoma is the fifth most common type of cancer in men and the sixth in women. Current treatment modalities, depending on the cancer stage, consist primarily of surgical excision, chemotherapy, adjuvant therapy, targeted therapies, and immunotherapy. Despite the wide range of therapeutic options and the steadily increasing response rates, a large subset of the treated patients relapse and develop resistance to further treatments. One novel approach in preclinical and clinical trials in immunotherapy is the adaptation of natural killer (NK) cells against resistant cancer cells. NK cells can kill a variety of cancer cell types, as well as the cancer stem cells, while leaving normal cells intact. In skin melanoma, as in most cancers, NK cells in the tumor microenvironment (TME) are functionally impaired. Several factors underlie the defective cause of NK cells, one of which is the dysregulation of the activating receptor NKG2D. This is the dominant receptor in regulating the cytotoxic activity, cytokine production, and regulation of other receptors expressed on NK cells and other lymphocytes. The defective NK cells in cancer models were associated with tumor growth and metastasis. In this review, we discuss the role of NK cells and their phenotypic variants in skin melanoma. Using bioinformatics, we have further analyzed the expression of NKG2D, confirming its low transcript levels in patients with skin melanoma. Furthermore, we show that the CD133 subset of cancer stem cells expresses low levels of NKG2D. Based on these findings we discuss the potential therapeutic approaches that can be exploited to upregulate NKG2D in patients' NK cells and restore their anti-melanoma effects, resulting in tumor regression and prolonged survival.

Vivid Memories of Sercarz's Traineeship and Am Indebted to Him for My Professional Career.

I am writing this chapter to reflect of my memories spanning at the time that I have first met the late Eli Sercarz and succeeded to earn my PhD degree under his titulage and traineeship. My first experience was at the time when Eli was recruited at UCLA as a new Assistant Professor in Immunology and I was in my undergraduate senior year. His teaching course in Fundamental Immunology was revolutionary at the time as prior teaching in immunology was primarily basic serology. I was mesmerized by the subject and decided that my professional career will be in immunology and received my PhD in Eli's laboratory. My research thesis consisted of two related topics. 1. Characterization of the immunogenic, tolerogenic and cryptic epitopes in selectively fragmented hen egg-white lysozyme (HEL) peptide fragments. 2. Analyzing and characterizing human and rabbit tear lysozymes as well as investigating the transport of various antibody isotypes from the serum to the tear. In addition, isolating and characterizing a novel specific tear prealbumin in the tear. This review describes my journey in Eli Sercarz's laboratory and my sincere indebtness of my academic career which was the result of his input and care.

YY1 Silencing Induces 5-Fluorouracil-Resistance and BCL2L15 Downregulation in Colorectal Cancer Cells: Diagnostic and Prognostic Relevance.

Colorectal cancer (CRC) is characterized by genetic heterogeneity and is often diagnosed at an advanced stage. Therefore, there is a need to identify novel predictive markers. Yin Yang 1 (YY1) is a transcription factor playing a dual role in cancer. The present study aimed to investigate whether YY1 expression levels influence CRC cell response to therapy and to identify the transcriptional targets involved. The diagnostic and prognostic values of YY1 and the identified factor(s) in CRC patients were also explored. Silencing of YY1 increased the resistance to 5-Fluorouracil-induced cytotoxicity in two out of four CRC cells with different genotypes. BCL2L15/Bfk pro-apoptotic factor was found selectively expressed in the responder CRC cells and downregulated upon YY1 knockdown. CRC dataset analyses corroborated a tumor-suppressive role for both YY1 and BCL2L15 whose expressions were inversely correlated with aggressiveness. CRC single-cell sequencing dataset analyses demonstrated higher co-expression levels of both YY1 and BCL2L15 within defined tumor cell clusters. Finally, elevated levels of YY1 and BCL2L15 in CRC patients were associated with larger relapse-free survival. Given their observed anti-cancer role, we propose YY1 and BCL2L15 as candidate diagnostic and prognostic CRC biomarkers.

Identifying Crosstalk between Raf Kinase Inhibitor Protein and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which hyperactive autoantibodies attack and damage healthy tissues and organs. SLE can affect multiple organs, such as the skin, kidneys, joints, and brain. The pathogenesis of SLE is multifaceted and complex, making it difficult to develop targeted therapies to ameliorate symptoms and the onset of disease. A number of signaling pathways have been investigated and shown to be implicated in SLE; however, information regarding the specific pathways involved, at least in part, in the pathogenesis of SLE remains scarce. The role of Raf kinase inhibitor protein (RKIP) in key signaling pathways in cancer is well-studied. However, studies highlighting the role of RKIP in autoimmune diseases and the inflammatory response are emerging. Whereas the induction of RKIP in cancer is associated with improved responses and reduced resistance, the overexpression of RKIP in normal tissues inhibits inflammatory cytokines and chemokines and may also inhibit autoimmunity. In this review, we have analyzed the potential crosstalk between the signaling pathways that regulate SLE and RKIP and whether targeting the pathways that activate the expression of RKIP may prove to be a novel therapeutic tool against the pathogenesis of SLE.

Involvement of Yin Yang 1 (YY1) Expression in T-Cell Subsets Differentiation and Their Functions: Implications in T Cell-Mediated Diseases.

The transcription factor Yin Yang 1 (YY1) has been implicated in embryogenesis, cell differentiation, organ development, and regulation of T cell-mediated immune diseases. YY1 has been reported to act as an activator or repressor, or both, of various genes depending on the nature of the tissue and their context. Although the roles of YY1 in both pathogenesis and progression of tumors has been the subject of many reports, the roles of YY1 in the immune system are not as well known. In this review, we examine the literature on the role of YY1 in both the differentiation and the development of various subsets of the T lymphocytes and examined its molecular role in these areas. We examined the role of YY1 in the thymus for the development of both CD4 and CD8 T lymphocytes, the various CD4 subsets, Th1, Th2, Th17, and Treg. Our analyses revealed that the presence of YY1 is necessary for maturation and proliferation of the αß lineage through its role in mediating the apoptotic pathway. Moreover, in differentiation of T cell subsets, YY1 controls the expression of the Th2 master regulator GATA3, the Treg inducer Foxp3, as well as IL-12 expression, which is important in regulating production of Th1 cytokines. Furthermore, the role of YY1 in the Th17 signaling pathway has not been fully identified, although recent studies have suggested that differentiation of Th17 involves synergistic action of YY1 and STAT3. The previously mentioned findings strongly suggest that the role of YY1 in T cells is critical in both their normal differentiation and the induction of T cell-mediated autoimmune diseases. Clearly, such findings suggest the potential therapeutic applications of YY1 inhibitors to alleviate its role in autoimmune diseases.

YY1 regulates cancer cell immune resistance by modulating PD-L1 expression.

Recent advances in the treatment of various cancers have resulted in the adaptation of several novel immunotherapeutic strategies. Notably, the recent intervention through immune checkpoint inhibitors has resulted in significant clinical responses and prolongation of survival in patients with several therapy-resistant cancers (melanoma, lung, bladder, etc.). This intervention was mediated by various antibodies directed against inhibitory receptors expressed on cytotoxic T-cells or against corresponding ligands expressed on tumor cells and other cells in the tumor microenvironment (TME). However, the clinical responses were only observed in a subset of the treated patients; it was not clear why the remaining patients did not respond to checkpoint inhibitor therapies. One hypothesis stated that the levels of PD-L1 expression correlated with poor clinical responses to cell-mediated anti-tumor immunotherapy. Hence, exploring the underlying mechanisms that regulate PD-L1 expression on tumor cells is one approach to target such mechanisms to reduce PD-L1 expression and, therefore, sensitize the resistant tumor cells to respond to PD-1/PD-L1 antibody treatments. Various investigations revealed that the overexpression of the transcription factor Yin Yang 1 (YY1) in most cancers is involved in the regulation of tumor cells' resistance to cell-mediated immunotherapies. We, therefore, hypothesized that the role of YY1 in cancer immune resistance may be correlated with PD-L1 overexpression on cancer cells. This hypothesis was investigated and analysis of the reported literature revealed that several signaling crosstalk pathways exist between the regulations of both YY1 and PD-L1 expressions. Such pathways include p53, miR34a, STAT3, NF-kB, PI3K/AKT/mTOR, c-Myc, and COX-2. Noteworthy, many clinical and pre-clinical drugs have been utilized to target these above pathways in various cancers independent of their roles in the regulation of PD-L1 expression. Therefore, the direct inhibition of YY1 and/or the use of the above targeted drugs in combination with checkpoint inhibitors should result in enhancing the cell-mediated anti-tumor cell response and also reverse the resistance observed with the use of checkpoint inhibitors alone.

Role of the Transcription Factor Yin Yang 1 and Its Selectively Identified Target Survivin in High-Grade B-Cells Non-Hodgkin Lymphomas: Potential Diagnostic and Therapeutic Targets.

B-cell non-Hodgkin lymphomas (B-NHLs) are often characterized by the development of resistance to chemotherapeutic drugs and/or relapse. During drug-induced apoptosis, Yin Yang 1 (YY1) transcription factor might modulate the expression of apoptotic regulators genes. The present study was aimed to: (1) examine the potential oncogenic role of YY1 in reversing drug resistance in B-NHLs; and (2) identify YY1 transcriptional target(s) that regulate the apoptotic pathway in B-NHLs. Predictive analyses coupled with database-deposited data suggested that YY1 binds the promoter of the BIRC5/survivin anti-apoptotic gene. Gene Expression Omnibus (GEO) analyses of several B-NHL repositories revealed a conserved positive correlation between YY1 and survivin, both highly expressed, especially in aggressive B-NHLs. Further validation experiments performed in Raji Burkitt's lymphomas cells, demonstrated that YY1 silencing was associated with survivin downregulation and sensitized the cells to apoptosis. Overall, our results revealed that: (1) YY1 and survivin are positively correlated and overexpressed in B-NHLs, especially in BLs; (2) YY1 strongly binds to the survivin promoter, hence survivin may be suggested as YY1 transcriptional target; (3) YY1 silencing sensitizes Raji cells to drug-induced apoptosis via downregulation of survivin; (4) both YY1 and survivin are potential diagnostic markers and therapeutic targets for the treatment of resistant/relapsed B-NHLs.

Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer.

Several gene products have been postulated to mediate inherent and/or acquired anticancer drug resistance and tumor metastasis. Among these, the metastasis suppressor and chemo-immuno-sensitizing gene product, Raf Kinase Inhibitor Protein (RKIP), is poorly expressed in many cancers. In contrast, the metastasis inducer and chemo-immuno-resistant factor Yin Yang 1 (YY1) is overexpressed in many cancers. This inverse relationship between RKIP and YY1 expression suggests that these two gene products may be regulated via cross-talks of molecular signaling pathways, culminating in the expression of different phenotypes based on their targets. Analyses of the molecular regulation of the expression patterns of RKIP and YY1 as well as epigenetic, post-transcriptional, and post-translational regulation revealed the existence of several effector mechanisms and crosstalk pathways, of which five pathways of relevance have been identified and analyzed. The five examined cross-talk pathways include the following loops: RKIP/NF-κB/Snail/YY1, p38/MAPK/RKIP/GSK3ß/Snail/YY1, RKIP/Smurf2/YY1/Snail, RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1, as well as RKIP/GPCR/STAT3/miR-34/YY1. Each loop is comprised of multiple interactions and cascades that provide evidence for YY1's negative regulation of RKIP expression and vice versa. These loops elucidate potential prognostic motifs and targets for therapeutic intervention. Chiefly, these findings suggest that targeted inhibition of YY1 by specific small molecule inhibitors and/or the specific induction of RKIP expression and activity are potential therapeutic strategies to block tumor growth and metastasis in many cancers, as well as to overcome anticancer drug resistance. These strategies present potential alternatives for their synergistic uses in combination with low doses of conventional chemo-immunotherapeutics and hence, increasing survival, reducing toxicity, and improving quality of life.

Crosstalks between Raf-kinase inhibitor protein and cancer stem cell transcription factors (Oct4, KLF4, Sox2, Nanog).

Raf-kinase inhibitor protein has been reported to inhibit both the Raf/mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase and nuclear factor kappa-light-chain of activated B cells pathways. It has also been reported in cancers that Raf-kinase inhibitor protein behaves as a metastatic suppressor as well as a chemo-immunosensitizing factor to drug/immune-mediated apoptosis. The majority of cancers exhibit low or no levels of Raf-kinase inhibitor protein. Hence, the activities of Raf-kinase inhibitor protein contrast, in part, to those mediated by several cancer stem cell transcription factors for their roles in resistance and metastasis. In this review, the existence of crosstalks in the signaling pathways between Raf-kinase inhibitor protein and several cancer stem cell transcription factors (Oct4, KLF4, Sox2 and Nanog) was assembled. Oct4 is induced by Lin28, and Raf-kinase inhibitor protein inhibits the microRNA binding protein Lin28. The expression of Raf-kinase inhibitor protein inversely correlates with the expression of Oct4. KLF4 does not interact directly with Raf-kinase inhibitor protein, but rather interacts indirectly via Raf-kinase inhibitor protein's regulation of the Oct4/Sox2/KLF4 complex through the mitogen-activated protein kinase pathway. The mechanism by which Raf-kinase inhibitor protein inhibits Sox2 is via the inhibition of the mitogen-activated protein kinase pathway by Raf-kinase inhibitor protein. Thus, Raf-kinase inhibitor protein's relationship with Sox2 is via its regulation of Oct4. Inhibition of extracellular signal-regulated kinase by Raf-kinase inhibitor protein results in the upregulation of Nanog. The inhibition of Oct4 by Raf-kinase inhibitor protein results in the failure of the heterodimer formation of Oct4 and Sox2 that is necessary to bind to the Nanog promoter for the transcription of Nanog. The findings revealed that there exists a direct correlation between the expression of Raf-kinase inhibitor protein and the expression of each of the above transcription factors. Based on these analyses, we suggest that the expression level of Raf-kinase inhibitor protein may be involved in the regulation of the cancer stem cell phenotype.

P38 MAPK expression and activation predicts failure of response to CHOP in patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: The p38 MAPK is constitutively activated in B-NHL cell lines and regulates chemoresistance. Accordingly, we hypothesized that activated p38 MAPK may be associated with the in vivo unresponsiveness to chemotherapy in B-NHL patients. METHODS: Tissue microarrays generated from eighty untreated patients with Diffused Large B Cell Lymphoma (DLBCL) were examined by immunohistochemistry for the expression of p38 and phospho p38 (p-p38) MAPK. In addition, both Bcl-2 and NF-κB expressions were determined. Kaplan Meier analysis was assessed. RESULTS: Tumor tissues expressed p38 MAPK (82 %) and p-p38 MAPK (30 %). Both p38 and p-p38 MAPK expressions correlated with the high score performance status. A significant correlation was found between the expression p-p38 and poor response to CHOP. The five year median follow-up FFS was 81 % for p38(-) and 34 % for p38(+) and for OS was 83 % for p38(-) and 47 % for p38(+). The p-p38(+) tissues expressed Bcl-2 and 90 % of p-p38(-) where Bcl-2(-). The coexpression of p-p38 and Bcl-2 correlated with pool EFS and OS. There was no correlation between the expression of p-p38 and the expression of NF-κB. CONCLUSION: The findings revealed, for the first time, that a subset of patients with DLBCL and whose tumors expressed high p-p38 MAPK responded poorly to CHOP therapy and had poor EFS and OS. The expression of p38, p-p38, Bcl2 and the ABC subtype are significant risk factors both p38 and p-p38 expressions remain independent prognostic factors.

Repeated sub-optimal photodynamic treatments with pheophorbide a induce an epithelial mesenchymal transition in prostate cancer cells via nitric oxide.

Photodynamic therapy (PDT) is a clinically approved treatment that causes a selective cytotoxic effect in cancer cells. In addition to the production of singlet oxygen and reactive oxygen species, PDT can induce the release of nitric oxide (NO) by up-regulating nitric oxide synthases (NOS). Since non-optimal PDT often causes tumor recurrence, understanding the molecular pathways involved in the photoprocess is a challenging task for scientists. The present study has examined the response of the PC3 human metastatic prostate cancer cell line following repeated low-dose pheophorbide a treatments, mimicking non-optimal PDT treatment. The analysis was focused on the NF-kB/YY1/RKIP circuitry as it is (i) dysregulated in cancer cells, (ii) modulated by NO and (iii) correlated with the epithelial to mesenchymal transition (EMT). We hypothesized that a repeated treatment of non-optimal PDT induces low levels of NO that lead to cell growth and EMT via the regulation of the above circuitry. The expressions of gene products involved in the circuitry and in EMT were analyzed by western blot. The findings demonstrate the cytoprotective role of NO following non-optimal PDT treatments that was corroborated by the use of L-NAME, an inhibitor of NOS.

Immune Evasion in Cancer Is Regulated by Tumor-Asociated Macrophages (TAMs): Targeting TAMs.

Recent advancements in cancer treatment have explored a variety of approaches to address the needs of patients. Recently, immunotherapy has evolved as an efficacious treatment for various cancers resistant to conventional therapies. Hence, significant milestones in immunotherapy were achieved clinically in a large subset of cancer patients. Unfortunately, some cancer types do not respond to treatment, and among the responsive cancers, some patients remain unresponsive to treatment. Consequently, there is a critical need to examine the mechanisms of immune resistance and devise strategies to target immune suppressor cells or factors, thereby allowing for tumor sensitivity to immune cytotoxic cells. M2 macrophages, also known as tumor-associated macrophages (TAMs), are of interest due to their role in suppressing the immune system and influencing antitumor immune responses through modulating T cell activity and immune checkpoint expression. TAMs are associated with signaling pathways that modulate the tumor microenvironment (TME), contributing to immune evasion. One approach targets TAMs, focusing on preventing the polarization of M1 macrophages into the protumoral M2 phenotype. Other strategies focus on direct or indirect targeting of M2 macrophages through understanding the interaction of TAMs with immune factors or signaling pathways. Clinically, biomarkers associated with TAMs' immune resistance in cancer patients have been identified, opening avenues for intervention using pharmacological agents or immunotherapeutic approaches. Ultimately, these multifaceted approaches are promising in overcoming immune resistance and improving cancer treatment outcomes.

Polarization of M2 Tumor-Associated Macrophages (TAMs) in Cancer Immunotherapy.

We have witnessed in the last decade new milestones in the treatment of various resistant cancers with new immunotherapeutic modalities. These advances have resulted in significant objective durable clinical responses in a subset of cancer patients. These findings strongly suggested that immunotherapy should be considered for the treatment of all subsets of cancer patients. Accordingly, the mechanisms underlying resistance to immunotherapy must be explored and develop new means to target these resistant factors. One of the pivotal resistance mechanisms in the tumor microenvironment (TME) is the high infiltration of tumor-associated macrophages (TAMs) that are highly immunosuppressive and responsible, in large part, of cancer immune evasion. Thus, various approaches have been investigated to target the TAMs to restore the anti-tumor immune response. One approach is to polarize the M2 TAMS to the M1 phenotype that participates in the activation of the anti-tumor response. In this review, we discuss the various and differential properties of the M1 and M2 phenotypes, the molecular signaling pathways that participate in the polarization, and various approaches used to target the polarization of the M2 TAMs into the M1 anti-tumor phenotype. These approaches include inhibitors of histone deacetylases, PI3K inhibitors, STAT3 inhibitors, TLR agonists, and metabolic reprogramming. Clearly, due to the distinct features of various cancers and their heterogeneities, a single approach outlined above might only be effective against some cancers and not others. In addition, targeting by itself may not be efficacious unless used in combination with other therapeutic modalities.

The Role of TAMs in the Regulation of Tumor Cell Resistance to Chemotherapy.

Tumor-associated macrophages (TAMs) are the predominant cell infiltrate in the immunosuppressive tumor microenvironment (TME). TAMs are central to fostering pro-inflammatory conditions, tumor growth, metastasis, and inhibiting therapy responses. Many cancer patients are innately refractory to chemotherapy and or develop resistance following initial treatments. There is a clinical correlation between the level of TAMs in the TME and chemoresistance. Hence, the pivotal role of TAMs in contributing to chemoresistance has garnered significant attention toward targeting TAMs to reverse this resistance. A prerequisite for such an approach requires a thorough understanding of the various underlying mechanisms by which TAMs inhibit response to chemotherapeutic drugs. Such mechanisms include enhancing drug efflux, regulating drug metabolism and detoxification, supporting cancer stem cell (CSCs) resistance, promoting epithelial-mesenchymal transition (EMT), inhibiting drug penetration and its metabolism, stimulating angiogenesis, impacting inhibitory STAT3/NF-κB survival pathways, and releasing specific inhibitory cytokines including TGF-ß and IL-10. Accordingly, several strategies have been developed to overcome TAM-modulated chemoresistance. These include novel therapies that aim to deplete TAMs, repolarize them toward the anti-tumor M1-like phenotype, or block recruitment of monocytes into the TME. Current results from TAM-targeted treatments have been unimpressive; however, the use of TAM-targeted therapies in combination appears promising These include targeting TAMs with radiotherapy, chemotherapy, chemokine receptor inhibitors, immunotherapy, and loaded nanoparticles. The clinical limitations of these strategies are discussed.