Accumulating evidence demonstrates that tumor-associated macrophages (TAMs) are central regulators of cancer progression rather than passive components of tumor inflammation. Advances in single-cell and spatial technologies have revealed that macrophages actively shape tumor initiation, growth, immune evasion, angiogenesis, and metastasis through context-dependent programs governed by developmental origin, microenvironmental cues, metabolic constraints, and epigenetic remodeling. Tumors exploit the inherent plasticity of macrophages, reprogramming them into diverse functional states that support malignant expansion and therapeutic resistance. This chapter provides an integrated framework for understanding TAM biology across multiple regulatory dimensions, including ontogeny, plasticity, metabolism, epigenetic control, and spatial niche organization. We examine how embryonic-derived and monocyte-derived macrophages acquire distinct identities, how tumor ecosystems sculpt macrophage behavior through cytokine, metabolic, and mechanical signals, and how spatial localization within tumors generates specialized macrophage subsets with nonredundant functions. Emerging insights from spatial transcriptomics, intravital imaging, and multiomic profiling are discussed as transformative tools that redefine macrophage classification and function in human cancer. Finally, we synthesize current and emerging therapeutic strategies targeting TAM recruitment, survival, reprogramming, and phagocytic function, including metabolic and epigenetic interventions, immune checkpoint modulation, and macrophage-engineered cell therapies. By integrating mechanistic biology with translational and clinical perspectives, this chapter highlights tumor-associated macrophages as programmable determinants of tumor behavior and as critical targets for next-generation precision oncology.

The dysregulation of tumorigenesis at the epigenetic level entails erratic gene expression, in which changes do not rely on alterations to the genetic sequence. Such changes are often orchestrated by mechanisms that involve modifying DNA or the histones that package it, as well as interrupting or suppressing microRNAs. For instance, tumor suppressor genes may be turned off, oncogenes can be turned on, or the genes affecting cellular genetic stability may be damaged recognizably, i.e., with certain patterns of expression, such as the hypermethylation of the BRCA1 gene in some types of breast cancer or such as the hypermethylation of the BRCA1 gene in some types of breast cancer or the combination of promoter-specific hypermethylation and global hypomethylation that characterizes many colorectal cancers. The so-called "social determinants of health (SDOH)," which also have been shown to include aspects of physical and social environments such as exposure to pollution, food insecurity, and the compounding of health-threatening factors due to chronic stress, are one of the key players in the story of the epigenome and cancer. The review aims to address how these cancer-causing factors alter the epigenome, particularly in the context of social determinants of health. If we wish to prevent and treat cancer among the socially disadvantaged, we must reshape research and policy in a global way. For the prevention and treatment of cancer, an advanced understanding of epigenetic analysis is needed.

Microsomal glutathione transferase 1 (MGST1), a membrane-associated enzyme of the MAPEG family, has emerged as a central regulator of ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxide accumulation. Traditionally recognized for its roles in detoxification and oxidative stress responses, MGST1 has recently been identified as a key suppressor of ferroptosis through multiple mechanisms, including glutathione-dependent reduction of lipid hydroperoxides, inhibition of arachidonate 5-lipoxygenase activity, modulation of iron availability through melanin-associated sequestration, and integration with transcriptional, epigenetic, post-translational, and signaling networks. This review summarizes the structural and enzymatic properties of MGST1, its subcellular localization at the endoplasmic reticulum and outer mitochondrial membrane, and its diverse regulatory mechanisms in ferroptosis control. In cancer, elevated MGST1 promotes tumor cell survival, proliferation, metastasis, immune evasion, and resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy by buffering lipid peroxidation and limiting ferroptotic death. Conversely, in non-malignant diseases, including myocardial ischemia-reperfusion injury, neurotoxicity, acute pancreatitis, intervertebral disc degeneration, diabetic cardiomyopathy, and inflammatory disorders, MGST1 may protect vulnerable tissues from ferroptosis-associated injury. These context-dependent functions create a therapeutic paradox: MGST1 inhibition may enhance cancer treatment efficacy, whereas MGST1 activation may preserve normal tissue integrity in degenerative or ischemic conditions. Emerging strategies include small-molecule inhibitors, gene interference, epigenetic modulation, NRF2-mediated activation, and combination approaches with existing therapies. MGST1 also holds promise as a diagnostic, prognostic, and treatment-stratification biomarker. Overall, MGST1 represents a pivotal ferroptosis regulator with broad translational relevance.

Advanced prostate cancer is one of the leading causes of cancer mortality in men and is often characterized by disease progression through therapeutic evasion followed by metastasis. Emerging evidence suggests that cancer-nerve crosstalk can influence the tumor microenvironment and promotes aggressive disease behavior. Neural infiltration within prostate tumors favors cancer-nerve crosstalk and therefore can establish a reciprocal exchange of growth factors, chemokines, neurotransmitters, and neurotrophic clues, which leads to tumor growth, therapy resistance, and the development of neuropathic symptoms. In advanced prostate cancer, neural infiltration mediated aberrant signaling within the cancer cells associated with poor clinical prognosis. Therapeutic intervention of locally advanced prostate cancer generates various neurological complications associated with peripheral neuropathy. Conversely, prolonged androgen receptor inhibition or chemotherapies in late-stage prostate cancer are associated with central nervous system complications such as altered neuronal activity, cognitive impairment, mood disturbances, and reduced quality of life. Therefore, preservation of neural integrity during prostate cancer therapy is in high demand to minimize nerve-related complications. However, conventional systemic therapies failed to prevent treatment-associated neural damage. Therefore, targeted therapies are in high demand to mitigate drug-related adverse effects. In this aspect, oncolytic viral therapy could represent a promising approach to aid selective killing of cancer cells. In the future, these could be emerging as viable candidates for first-line therapeutic intervention.

Formation of distant tumors from initial primary sites, metastasis, is a principal cause of cancer-related mortality from solid cancers and is associated with poor clinical and surgical outcomes. The development of a pre-metastatic niche precedes organ-specific metastatic colonization and serves as a central determinant of metastatic progression. The evolution of pre-metastatic niche research has expanded our understanding of how primary tumors prime distant organs for metastatic colonization. Progress from descriptive observations to mechanistic insights has clarified the cellular and molecular factors that create permissive secondary microenvironments. These findings have identified critical pathways that regulate pre-metastatic niche formation and support the development of strategies to prevent metastatic progression. A critical element in reprogramming the tumor microenvironment involves exosomes, cell-derived extracellular vesicles (EVs) enriched in proteins, nucleic acids, and lipids. These vesicles mediate intercellular communication and actively remodel local and systemic microenvironments. Exosomes play essential roles in tumor metastasis, a leading cause of cancer-related mortality from advancing solid cancers. Circulating tumor-derived exosomes promote metastatic initiation and progression and contribute to organotropism by directing metastatic spread to specific distant sites. Advances in exosome biology and engineering have enabled the development of novel strategies for therapeutic intervention. In this review, we summarize recent progress in comprehending exosome-mediated regulation of metastasis, with an emphasis on fundamental mechanisms and emerging approaches for therapeutic targeting in advanced cancers.

Drug repurposing refers to the process of using an existing drug or drug candidate for a new treatment or medical condition for which it was not indicated before. The process of "drug repurposing" usually involves an FDA-approved entity which has undergone clinical development and have a with well-established safety and toxicity profile in patients. Several convergent studies show that repurposed drugs may present a promising strategy for the management and therapy of several human cancers. Memantine is used to combat dementia in moderate-to-severe Alzheimer's disease (AD) patients. Several convergent studies show that memantine (and its analogs) may have applications in multiple disease conditions associated with human cancers. Memantine and its related compounds have shown promise as neuroprotective agents, anti-fatigue agents and pain-relieving agents to alleviate the toxic side effects of radiation therapy and chemotherapy. Recent publications have revealed that memantine displays anti-cancer activity by exerting direct growth-suppressive activity on the primary tumor as modulating the genomic/cellular landscape of the tumor microenvironment. Currently, clinical trials are in progress, which aim to evaluate the potential applications of memantine in cancer treatment. The adamantane scaffold in memantine has proved to be a versatile tool for the discovery of synthetic memantine analogs with robust anti-cancer activity. The discovery of second-generation memantine analogs may have wider applications in combating cancer recurrence and addressing clinical challenges in the treatment of drug-resistant and metastatic cancers.

Viruses have been developed as oncolytic immunotherapy agents due to their ability to target and kill cancer cells while sparing normal cells. Additionally, engineered oncolytic viruses (OVs) can alter the immunosuppressive tumor microenvironment, making other cancer therapies more favorable. Many candidate OVs are currently in clinical trials as monotherapy or in combination with other cancer therapeutics. Oncolytic myxoma virus (MYXV), a member of the Poxviridae family that infects only leporids in nature and causes no infection to humans or other animals, has been developed as an oncolytic immunotherapy agent. MYXV selectively infects cancer cells due to the accumulation of mutations and the absence of functional antiviral responses within these cells. The large dsDNA genome of MYXV is amenable to the deletion of non-essential immunomodulatory genes and to the insertion of multiple immunostimulatory transgenes with antitumor properties. The systemic and local administration of engineered MYXV promotes changes within the tumor microenvironment that reverse immunosuppression and improve immune activation and infiltration. These cancer tropism and immune activation properties, combined with the absence of preexisting antibodies, led to the testing of MYXV in various types of preclinical cancer models, including pancreatic cancer, glioblastoma, ovarian cancer, melanoma, small cell lung cancer, and hematological malignancies. This review highlights the current progress with the development of MYXV as an immunotherapeutic agent.

Cancer terminator viruses (CTVs) are next‑generation conditionally replicating oncolytic adenoviruses that integrate precise tumor targeting, direct oncolysis, and potent cytokine‑mediated immunotherapy into a single platform. In CTVs, viral replication is driven by cancer‑selective promoters such as the progression elevated gene‑3 (PEG‑3) promoter, restricting E1A expression and adenoviral replication to tumor cells while sparing normal tissues. These vectors are "armed" with broad‑acting immunomodulatory cytokines, most notably melanoma differentiation-associated gene‑7/interleukin‑24 (mda‑7/IL‑24) or interferon‑gamma, which can induce cancer‑selective apoptosis, toxic autophagy, anti‑angiogenesis, and robust innate and adaptive immune responses, including "bystander killing" of distant, noninfected tumor cells. Chimeric fiber‑modified backbones such as Ad.5/3 enhance infection of Coxsackie-adenovirus receptor-deficient tumors, broadening applicability to refractory epithelial, prostate, brain, and pancreatic cancers. Preclinical studies demonstrate that CTVs eradicate primary and metastatic lesions in multiple xenograft models and synergize with chemotherapy, radiotherapy, and immune checkpoint inhibitors, especially when combined with advanced delivery technologies such as ultrasound‑targeted microbubble destruction and focused ultrasound double-microbubble platforms for systemic, site‑directed release. Ongoing efforts to incorporate IL‑24 "Superkine," fusion cytokines and fusion Superkines, and rational combinations with immunotherapies position CTVs as a versatile and clinically translatable viro-immunotherapeutic strategy for advanced solid tumors. Progress in these efforts will pave the way for applying these virotherapies for improved cancer treatments in the clinic.

Viruses are extraordinary products of evolution that can be harnessed as versatile platforms for cancer therapy. They replicate in tumor cells, induce lysis, and stimulate antitumor immunity. Among viral platforms, oncolytic adenoviruses (OAds) have emerged as leading candidates. They are well-characterized, amenable to genetic modification, capable of accommodating large payloads, and can be produced at high titers. Nonetheless, natural adenoviruses require precise engineering to maximize therapeutic benefit. Clinical translation has also been constrained by several barriers, including the absence of murine models permissive for adenovirus replication, immune neutralization during systemic delivery, and insufficient tumor penetration. This chapter explores strategies to overcome these challenges, beginning with an overview of the adenovirus replication cycle and its interaction with host cells and systemic factors. We discuss the intrinsic properties of the adenoviral life cycle that make these vectors effective oncolytic agents, as well as genetic modifications designed to further enhance antitumor efficacy. These include receptor retargeting, replication control, insertion of therapeutic payloads, and capsid protein engineering to ablate unwanted interactions with host factors. We also highlight clinically advanced OAds to illustrate which modifications have successfully moved beyond laboratory development into clinical application. In addition, the potential of alternative adenovirus types with distinct seroprevalence, replication machinery, and blood interactions is reviewed. Finally, we discuss advances in preclinical modeling, emphasizing the limitations of murine models and highlighting the development of immunocompetent hamster and porcine models that better reproduce adenovirus-host interactions and provide critical insights for clinical translation of OAds.

Reoviruses have emerged as promising oncolytic agents, exploiting their natural tropism for transformed cells with aberrant Ras signaling to enable selective replication and tumor cell lysis. The most clinically advanced candidate, Mammalian orthoreovirus Pelareorep (Reolysin), has demonstrated efficacy across multiple malignancies, including breast cancer, glioma, and pancreatic adenocarcinoma, with generally manageable safety profiles. Beyond Pelareorep, novel orthoreoviruses such as Avian orthoreovirus and Pteropine orthoreovirus have shown potent oncolytic activity and favorable tolerability in preclinical models, broadening the therapeutic landscape. Reovirus-based virotherapy exerts dual anti-tumor effects by inducing direct oncolysis and activating innate and adaptive immune responses, thereby enhancing outcomes when combined with chemotherapy or immune checkpoint inhibitors. Despite these advances, several barriers remain. Tumor heterogeneity and variable receptor expression affect viral infectivity and dissemination, while host immune responses, though critical for anti-tumor immunity, can also limit viral persistence and efficacy. Key mechanistic gaps persist in understanding reovirus-host interactions, particularly in immune modulation and cell death pathways. Furthermore, the optimal integration of reoviruses into combination regimens and clinical protocols requires further validation. Future efforts should emphasize biomarker-driven patient stratification, rational immunotherapeutic combinations to overcome tumor immunosuppression, and engineering of reovirus vectors to improve specificity and safety. Exploration of emerging orthoreoviruses with distinct biological properties also presents new opportunities for therapeutic innovation. Collectively, reoviruses represent a compelling platform at the forefront of precision oncolytic virotherapy, with translational potential hinging on the resolution of critical mechanistic and clinical challenges.

Current cancer therapies, including cytotoxic agents, molecularly targeted drugs, and immune-based treatments, are often constrained by therapeutic resistance, systemic toxicity, and inconsistent clinical efficacy. The adeno-associated virus (AAV) vector-based therapy emerges as a promising strategy to address these limitations, owing to its favorable safety profile and high degree of engineerability. AAV-based gene therapy development is expanding beyond the treatment of rare monogenic disorders to encompass chronic diseases and cancer conditions associated with a high disease burden, driven not only by advances in vector technology but also by strategic considerations such as development costs, clinical needs, and commercial viability. Although challenges such as pre-existing host immunity and limited transgene packaging capacity remain, recent advances in biotechnology are actively mitigating these barriers. This review highlights recent progress in AAV-based gene therapy for cancer challenges and discusses future directions for the implementation of AAV vectors as a next-generation therapeutic modality in oncology.

Vesicular stomatitis virus (VSV), an enveloped RNA virus that naturally infects livestock, has emerged as a highly versatile and potent platform for research purposes and, especially, for oncolytic virotherapy. The unique advantages of VSV as an oncolytic platform, including its rapid replication kinetics, strong cytolytic activity, its easily manipulated genome and ability to express foreign transgenes, and the ability to manufacture VSV at high concentrations, make this virus particularly well-suited as an oncolytic virus vector. This chapter provides a comprehensive overview of the biological and therapeutic foundations underlying the development of oncolytic VSV. It begins with the basic virology of VSV, including its genome organization, host range, and its inherent tumor specificity due to its sensitivity to type I interferons, allowing for preferential replication in cells that harbor impairments in antiviral responses, which is a hallmark of cancer. The principles of oncolytic virotherapy are outlined, emphasizing the multiple mechanisms of action, including direct tumor cell lysis and induction of local and systemic antitumor immunity. Examples of genetic engineering strategies to enhance efficacy and improve the translational potential are outlined. Finally, the current state of clinical development, highlighting completed and ongoing clinical trials evaluating recombinant oncolytic VSV vectors in various malignancies is summarized. Together, these basic principles, the extensive preclinical development spanning over 2 decades, and recent clinical advances underscore the promise of VSV as a next-generation oncolytic platform with substantial potential to transform cancer therapy through virus engineering and combinatorial immuno-oncology strategies.

While there are many choices among gene transfer vectors for basic or applied research, non-replicating adenoviruses are among the most studied. The virus is well suited for in vivo gene therapy since the vector can be produced with relatively high titers, is an efficient platform for in vivo modification of a variety of target cells and is relatively safe considering that the viral genome remains episomal. The production of adenoviral vectors is scalable and, once virus particles have been recovered, does not depend on the transfection of plasmids, a costly and laborious process to perform on large scale and with pharmaceutical quality. These vectors can be extensively modified to provide targeting at the level of transduction and transgene expression. The use of a non-replicating vector implies that it will not express viral proteins but instead can be modified to carry coding or non-coding sequences, including those that may be prejudicial to the life cycle of replicating viruses. Admittedly, immunogenicity of adenoviral vectors is an issue that requires careful consideration but may be leveraged to act as an adjuvant for vaccines or to overcome the immunosuppressive tumor microenvironment. Modifications also allow adenoviral vectors to act as important allies for achieving long-term expression. If viral replication is desired, non-replicating vectors can be paired with conditionally replicating adenovirus, thus providing the best of both approaches. To date, three cancer gene therapy products, Gendicine, Adstiladrin, and Papzimeos, that are based on non-replicating adenovirus have been approved for commercialization. As we will explore here, non-replicating adenoviral vectors continue to be developed for cancer gene therapy.

Glioblastoma (GBM) is a common, aggressive, primary brain tumor. New therapies are needed to improve outcomes in patients with this disease. One such approach which has shown preclinical promise is the use of genetically engineered Zika virus for oncolytic virotherapy. Zika virus is an enveloped, positive-sense, single-stranded RNA virus and is spread by mosquitoes of the Aedes genus. Most infections with Zika virus in adults are asymptomatic. However, primary infection with Zika virus early during pregnancy can cause fetal congenital defects. This phenomenon, termed congenital Zika syndrome, is thought to be the result of infection of fetal neural stem cells. The development of Zika virus as an oncolytic for GBM arose from the discovery that Zika virus infects and kills GBM stem cells. GBM stem cells have similarities to fetal neural stem cells and are a subpopulation of cells within the tumor that are refractory to treatment and likely drive tumor persistence and re-occurrence. In preclinical models of GBM, infection with Zika virus triggers immune-mediated clearance of orthotopically transplanted tumors and leads to development of immunological memory. The propensity of Zika virus to infect GBM stem cells along with limited systemic toxicities and transmissibility make Zika virus an ideal candidate for development as an oncolytic therapy.

Oncolytic viruses (OVs) are a rapidly expanding class of anti-neoplastic management options that utilize the innate infectivity of either native or modified viruses to preferentially lyse malignant cells while sparing healthy ones. Some OVs naturally target antigens within a tumor micro-environment, while others are re-oriented to identify specific targets via deletion of or addition to their existing genetic makeup. This chapter focuses on OVs in cutaneous oncology, providing an overview of their molecular mechanisms, clinical applications across a variety of disease states, and future directions for the field.