Targeting HDAC6 improves anti-CD47 immunotherapy.

BACKGROUND: Cancer cells can overexpress CD47, an innate immune checkpoint that prevents phagocytosis upon interaction with signal regulatory protein alpha (SIRPα) expressed in macrophages and other myeloid cells. Several clinical trials have reported that CD47 blockade reduces tumor growth in hematological malignancies. However, CD47 blockade has shown modest results in solid tumors, including melanoma. Our group has demonstrated that histone deacetylase 6 inhibitors (HDAC6is) have immunomodulatory properties, such as controlling macrophage phenotype and inflammatory properties. However, the molecular and cellular mechanisms controlling these processes are not fully understood. In this study, we evaluated the role of HDAC6 in regulating the CD47/SIRPα axis and phagocytosis in macrophages. METHODS: We tested the role of HDAC6is, especially Nexturastat A, in regulating macrophage phenotype and phagocytic function using bone marrow-derived macrophages and macrophage cell lines. The modulation of the CD47/SIRPα axis and phagocytosis by HDAC6is was investigated using murine and human melanoma cell lines and macrophages. Phagocytosis was evaluated via coculture assays of macrophages and melanoma cells by flow cytometry and immunofluorescence. Lastly, to evaluate the antitumor activity of Nexturastat A in combination with anti-CD47 or anti-SIRPα antibodies, we performed in vivo studies using the SM1 and/or B16F10 melanoma mouse models. RESULTS: We observed that HDAC6is enhanced the phenotype of antitumoral M1 macrophages while decreasing the protumoral M2 phenotype. In addition, HDAC6 inhibition diminished the expression of SIRPα, increased the expression of other pro-phagocytic signals in macrophages, and downregulated CD47 expression in mouse and human melanoma cells. This regulatory role on the CD47/SIRPα axis translated into enhanced antitumoral phagocytic capacity of macrophages treated with Nexturastat A and anti-CD47. We also observed that the systemic administration of HDAC6i enhanced the in vivo antitumor activity of anti-CD47 blockade in melanoma by modulating macrophage and natural killer cells in the tumor microenvironment. However, Nexturastat A did not enhance the antitumor activity of anti-SIRPα despite its modulation of macrophage populations in the SM1 tumor microenvironment. CONCLUSIONS: Our results demonstrate the critical regulatory role of HDAC6 in phagocytosis and innate immunity for the first time, further underscoring the use of these inhibitors to potentiate CD47 immune checkpoint blockade therapeutic strategies.

Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition.

Radiotherapy is a curative cancer treatment modality that imparts damage to cellular DNA, induces immunogenic cell death, and activates antitumor immunity. Despite the radiotherapy-induced direct antitumor effect seen within the treated volume, accumulating evidence indicates activation of innate antitumor immunity. Acute proinflammatory responses mediated by anticancer M1 macrophages are observed in the immediate aftermath following radiotherapy. However, after a few days, these M1 macrophages are converted to anti-inflammatory and pro-cancer M2 phenotype, leading to cancer resistance and underlying potential tumor relapse. Histone deacetylase 6 (HDAC6) plays a crucial role in regulating macrophage polarization and innate immune responses. Here, we report targeting HDAC6 function with a novel selective inhibitor (SP-2-225) as a potential therapeutic candidate for combination therapy with radiotherapy. This resulted in decreased tumor growth and enhanced M1/M2 ratio of infiltrating macrophages within tumors. These observations support the use of selective HDAC6 inhibitors to improve antitumor immune responses and prevent tumor relapse after radiotherapy.

Radiotherapy Induces Innate Immune Responses in Patients Treated for Prostate Cancers.

PURPOSE: Radiotherapy is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced radiotherapy technologies enable treatment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell-cycle arrest, cell death, and innate immune response (IIR) stimulation. EXPERIMENTAL DESIGN: To understand systemic clinical responses after radiation exposure, proteomic and metabolomic analyses were performed on plasma obtained from patients with cancer at intervals after prostate stereotactic body radiotherapy. Pathway and multivariate analyses were used to delineate molecular alterations following radiotherapy and its correlation with clinical outcomes. RESULTS: DNA damage response increased within the first hour after treatment and returned to baseline by 1 month. IIR signaling also increased within 1 hour of treatment but persisted for up to 3 months thereafter. Furthermore, robust IIR and metabolite elevations, consistent with an early proinflammatory M1-mediated innate immune activation, were observed in patients in remission, whereas patients experiencing prostate serum antigen-determined disease progression demonstrated less robust immune responses and M2-mediated metabolite elevations. CONCLUSIONS: To our knowledge, these data are the first report of longitudinal proteomic and metabolomic molecular responses in patients after radiotherapy for cancers. The data supports innate immune activation as a critical clinical response of patients receiving radiotherapy for prostate cancer. Furthermore, we propose that the observed IIR may be generalized to the treatment of other cancer types, potentially informing multidisciplinary therapeutic strategies for cancer treatment.

Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer.

BACKGROUND: Novel therapies are urgently needed for ovarian cancer (OC), the fifth deadliest cancer in women. Preclinical work has shown that DNA methyltransferase inhibitors (DNMTis) can reverse the immunosuppressive tumor microenvironment in OC. Inhibiting DNA methyltransferases activate transcription of double-stranded (ds)RNA, including transposable elements. These dsRNAs activate sensors in the cytoplasm and trigger type I interferon (IFN) signaling, recruiting host immune cells to kill the tumor cells. Adenosine deaminase 1 (ADAR1) is induced by IFN signaling and edits mammalian dsRNA with an A-to-I nucleotide change, which is read as an A-to-G change in sequencing data. These edited dsRNAs cannot be sensed by dsRNA sensors, and thus ADAR1 inhibits the type I IFN response in a negative feedback loop. We hypothesized that decreasing ADAR1 editing would enhance the DNMTi-induced immune response. METHODS: Human OC cell lines were treated in vitro with DNMTi and then RNA-sequenced to measure RNA editing. Adar1 was stably knocked down in ID8 Trp53-/- mouse OC cells. Control cells (shGFP) or shAdar1 cells were tested with mock or DNMTi treatment. Tumor-infiltrating immune cells were immunophenotyped using flow cytometry and cell culture supernatants were analyzed for secreted chemokines/cytokines. Mice were injected with syngeneic shAdar1 ID8 Trp53-/- cells and treated with tetrahydrouridine/DNMTi while given anti-interferon alpha and beta receptor 1, anti-CD8, or anti-NK1.1 antibodies every 3 days. RESULTS: We show that ADAR1 edits transposable elements in human OC cell lines after DNMTi treatment in vitro. Combining ADAR1 knockdown with DNMTi significantly increases pro-inflammatory cytokine/chemokine production and sensitivity to IFN-ß compared with either perturbation alone. Furthermore, DNMTi treatment and Adar1 loss reduces tumor burden and prolongs survival in an immunocompetent mouse model of OC. Combining Adar1 loss and DNMTi elicited the most robust antitumor response and transformed the immune microenvironment with increased recruitment and activation of CD8+ T cells. CONCLUSION: In summary, we showed that the survival benefit from DNMTi plus ADAR1 inhibition is dependent on type I IFN signaling. Thus, epigenetically inducing transposable element transcription combined with inhibition of RNA editing is a novel therapeutic strategy to reverse immune evasion in OC, a disease that does not respond to current immunotherapies.

CD137 agonist potentiates the abscopal efficacy of nanoparticle-based photothermal therapy for melanoma.

Despite the promise of immunotherapy such as the immune checkpoint inhibitors (ICIs) anti-PD-1 and anti-CTLA-4 for advanced melanoma, only 26%-52% of patients respond, and many experience grade III/IV immune-related adverse events. Motivated by the need for an effective therapy for patients non-responsive to clinically approved ICIs, we have developed a novel nanoimmunotherapy that combines locally administered Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) with systemically administered agonistic anti-CD137 monoclonal antibody therapy (aCD137). PBNP-PTT was administered at various thermal doses to melanoma cells in vitro, and was combined with aCD137 in vivo to test treatment effects on melanoma tumor progression, animal survival, immunological protection against tumor rechallenge, and hepatotoxicity. When administered at a melanoma-specific thermal dose, PBNP-PTT elicits immunogenic cell death (ICD) in melanoma cells and upregulates markers associated with antigen presentation and immune cell co-stimulation in vitro. Consequently, PBNP-PTT eliminates primary melanoma tumors in vivo, yielding long-term tumor-free survival. However, the antitumor immune effects generated by PBNP-PTT cannot eliminate secondary tumors, despite significantly slowing their growth. The addition of aCD137 enables significant abscopal efficacy and improvement of survival, functioning through activated dendritic cells and tumor-infiltrating CD8+ T cells, and generates CD4+ and CD8+ T cell memory that manifests in the rejection of tumor rechallenge, with no long-term hepatotoxicity. This study describes for the first time a novel and effective nanoimmunotherapy combination of PBNP-PTT with aCD137 mAb therapy for melanoma.

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers.

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma's susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.

Phase I Study of Entinostat in Combination with Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer.

LESSONS LEARNED: Entinostat at the selected dose levels in combination with a standard dose of enzalutamide showed a promising safety profile in this small phase I study BACKGROUND: Entinostat inhibits prostate cancer (PCa) growth and suppresses Treg cell function in vitro and in vivo. METHODS: This was a phase I study to explore the safety and preliminary efficacy of entinostat (3 and 5 mg orally per week) in combination with enzalutamide in castration resistant PCa (CRPC). The study was carried out in an open-label two-cohort design. Patients who had developed disease progression on or were eligible for enzalutamide were enrolled in the study. The safety profile of the combination therapy, Prostate specific antigen (PSA) levels, the pharmacokinetics of enzalutamide after entinostat administration, peripheral T-cell subtype (including Treg quantitation), and mononuclear cell (PBMC) histone H3 acetylation were analyzed. RESULTS: Six patients with metastatic CRPC were enrolled. There was no noticeable increment of fatigue related to entinostat. Toxicities possibly or probably related to entinostat or the combination therapy included grade 3 anemia 1/6 (17%), grade 2 white blood cell (WBC) decrease 1/6 (17%), and other self-limiting grade 1 adverse events (AEs). Median duration of treatment with entinostat was 18 weeks. Entinostat did not affect the steady plasma concentration of enzalutamide. Increased PBMC histone H3 acetylation was observed in blood samples. No evident T-cell subtype changes were detected, including in Treg quantitation. CONCLUSION: Entinostat 5 mg weekly in combination with enzalutamide showed an acceptable safety profile in this small phase I study. A planned phase II part of the trial was terminated because of sponsor withdrawal.

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019.

Immune cells of the monocyte/macrophage lineage are characterized by their diversity, plasticity, and variety of functions. Among them, macrophages play a central role in antiviral responses, tissue repair, and fibrosis. Macrophages can be reprogrammed by environmental cues, thus changing their phenotype during an antiviral immune response as the viral infection progresses. While M1-like macrophages are essential for the initial inflammatory responses, M2-like macrophages are critical for tissue repair after pathogen clearance. Numerous reports have evaluated the detrimental effects that coronaviruses, e.g., HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, have on the antiviral immune response and macrophage functions. In this review, we have addressed the breadth of macrophage phenotypes during the antiviral response and provided an overview of macrophage-coronavirus interactions. We also discussed therapeutic approaches to target macrophage-induced complications, currently under evaluation in clinical trials for coronavirus disease 2019 patients. Additionally, we have proposed alternative approaches that target macrophage recruitment, interferon signaling, cytokine storm, pulmonary fibrosis, and hypercoagulability.

Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models.

Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using in silico simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. In vitro characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. In vivo studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.

CpG-coated prussian blue nanoparticles-based photothermal therapy combined with anti-CTLA-4 immune checkpoint blockade triggers a robust abscopal effect against neuroblastoma.

High-risk neuroblastoma, which is associated with regional and systemic metastasis, is a leading cause of cancer-related mortality in children. Responding to this need for novel therapies for high-risk patients, we have developed a "nanoimmunotherapy," which combines photothermal therapy (PTT) using CpG oligodeoxynucleotide-coated Prussian blue nanoparticles (CpG-PBNPs) combined with anti-CTLA-4 (aCTLA-4) immunotherapy. Our in vitro studies demonstrate that in addition to causing ablative tumor cell death, our nanoimmunotherapy alters the surface levels of co-stimulatory, antigen-presenting, and co-inhibitory molecules on neuroblastoma tumor cells. When administered in a syngeneic, murine model of neuroblastoma bearing synchronous Neuro2a tumors, the CpG-PBNP-PTT plus aCTLA-4 nanoimmunotherapy elicits complete tumor regression in both primary (CpG-PBNP-PTT-treated) and secondary tumors, and long-term survival in a significantly higher proportion (55.5%) of treated-mice compared with the controls. Furthermore, the surviving, nanoimmunotherapy-treated animals reject Neuro2a rechallenge, suggesting that the therapy generates immunological memory. Additionally, the depletion of CD4+, CD8+, and NK+ populations abrogate the observed therapeutic responses of the nanoimmunotherapy. These findings demonstrate the importance of concurrent PTT-based cytotoxicity and the antitumor immune effects of PTT, CpG, and aCTLA-4 in generating a robust abscopal effect against neuroblastoma.

HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer.

Despite the outstanding clinical results of immune checkpoint blockade (ICB) in melanoma and other cancers, clinical trials in breast cancer have reported low responses to these therapies. Current efforts are now focused on improving the treatment efficacy of ICB in breast cancer using new combination designs such as molecularly targeted agents, including histone deacetylase inhibitors (HDACi). These epigenetic drugs have been widely described as potent cytotoxic agents for cancer cells. In this work, we report new noncanonical regulatory properties of ultra-selective HDAC6i over the expression and function of epithelial-mesenchymal transition pathways and the invasiveness potential of breast cancer. These unexplored roles position HDAC6i as attractive options to potentiate ongoing immunotherapeutic approaches. These new functional activities of HDAC6i involved regulation of the E-cadherin/STAT3 axis. Pretreatment of tumors with HDAC6i induced critical changes in the tumor microenvironment, resulting in improved effectiveness of ICB and preventing dissemination of cancer cells to secondary niches. Our results demonstrate for the first time that HDAC6i can both improve ICB antitumor immune responses and diminish the invasiveness of breast cancer with minimal cytotoxic effects, thus departing from the cytotoxicity-centric paradigm previously assigned to HDACi. SIGNIFICANCE: Ultraselective HDAC6 inhibitors can reduce tumor growth and invasiveness of breast cancer by noncanonical mechanisms unrelated to the previously cytotoxic properties attributed to HDAC inhibitors.

Actualización general de inmunoterapia en cáncer / Cancer immunotherapy: an update

Cancer is one of the leading causes of death worldwide. The success rate of conventional anticancer therapeutic approaches such as chemotherapy is limited by the non-specific toxicity and low specificity towards specific tumors, which are highly dependent on the mutational burden present on each patient. Similarly, targeted therapies have proven to induce resistance in numerous malignancies. Therefore, immunotherapy has emerged as a better approach to discriminate between "the own" and "the non-own", which occurs through two types of mechanisms, innate and acquired immunity. Acquired immunity is one of the targets for new immunotherapeutic treatments, unleashing the power of antigen-specific T cells as a potential therapeutic weapon for cancer treatment. Thus, immunotherapy modifies the own immune system to increase the recognition and elimination of cancer cells by identifying these cancer antigens. One of the advantages of immunotherapy, when compared to conventional anticancer approaches, is the generation of long-term immunity (immunological memory). Currently, there are different potential types of immunotherapy in cancer to promote the modulation of the immune response. Among them, the use of cytokines, vaccines, viruses, monoclonal antibodies, and the generation of adaptive immune response cells have achieved successful results in some types of cancer.

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.

Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53-/- ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment.

Indocyanine Green-Nexturastat A-PLGA Nanoparticles Combine Photothermal and Epigenetic Therapy for Melanoma.

In this study, we describe poly (lactic-co-glycolic) acid (PLGA)-based nanoparticles that combine photothermal therapy (PTT) with epigenetic therapy for melanoma. Specifically, we co-encapsulated indocyanine green (ICG), a PTT agent, and Nexturastat A (NextA), an epigenetic drug within PLGA nanoparticles (ICG-NextA-PLGA; INAPs). We hypothesized that combining PTT with epigenetic therapy elicits favorable cytotoxic and immunomodulatory responses that result in improved survival in melanoma-bearing mice. We utilized a nanoemulsion synthesis scheme to co-encapsulate ICG and NextA within stable and monodispersed INAPs. The INAPs exhibited concentration-dependent and near-infrared (NIR) laser power-dependent photothermal heating characteristics, and functioned as effective single-use agents for PTT of melanoma cells in vitro. The INAPs functioned as effective epigenetic therapy agents by inhibiting the expression of pan-histone deacetylase (HDAC) and HDAC6-specific activity in melanoma cells in vitro. When used for both PTT and epigenetic therapy in vitro, the INAPs increased the expression of co-stimulatory molecules and major histocompatibility complex (MHC) Class I in melanoma cells relative to controls. These advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. These findings demonstrate the potential of INAPs as agents of PTT and epigenetic therapy for melanoma.

[Cancer immunotherapy: an update]. / Actualización general de inmunoterapia en cáncer.

Cancer is one of the leading causes of death worldwide. The success rate of conventional anticancer therapeutic approaches such as chemotherapy is limited by the non-specific toxicity and low specificity towards specific tumors, which are highly dependent on the mutational burden present on each patient. Similarly, targeted therapies have proven to induce resistance in numerous malignancies. Therefore, immunotherapy has emerged as a better approach to discriminate between "the own" and "the non-own", which occurs through two types of mechanisms, innate and acquired immunity. Acquired immunity is one of the targets for new immunotherapeutic treatments, unleashing the power of antigen-specific T cells as a potential therapeutic weapon for cancer treatment. Thus, immunotherapy modifies the own immune system to increase the recognition and elimination of cancer cells by identifying these cancer antigens. One of the advantages of immunotherapy, when compared to conventional anticancer approaches, is the generation of long-term immunity (immunological memory). Currently, there are different potential types of immunotherapy in cancer to promote the modulation of the immune response. Among them, the use of cytokines, vaccines, viruses, monoclonal antibodies, and the generation of adaptive immune response cells have achieved successful results in some types of cancer.

Author Correction: Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models.

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy.

Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches.