The Art of Oncoimmunovaccinomics

The art of oncoimmunovaccinomics will be concisely explained herein. This scientific insight will explore its history cancer immunotherapy, the molecular basis of cancer immunotherapy, cancer immunotherapeutic approach, cancer immunosurveillance and immunoediting, the hallmarks of cancer (can be) revisited, nanotechnology-based cancer immunovaccinomics, the theory of and immunogenomic perspectives.


Introduction
There have been different cancer treatment modalities for a long time. Surgery, radiation, chemotherapy, targeted medications, and immunotherapy are the treatments available. Firstly, let us begin with a discussion of surgery. Surgery has been used to excise active tumor cells to avoid their development and spread since the 1800s. Even so, surgery has its drawbacks, such as the ineligibility of certain inaccessible tumors and the reduced efficacy of surgery if the tumor has already spread.
Secondly, let us reveal about radiation in a nutshell. Since the early 1900s, radiation has been used to destroy cancerous cells by using extremely focused X-rays or radioactive isotopes. Nevertheless, radiation has its restriction. It pos-sesses limited efficacy if tumor has already started to spread; in addition, it can be potentially harmful for vital organs juxtaposed tumors.
Thirdly, let us provide a brief overview of chemotherapy. Since the late 1940's, cytotoxic drugs have been used to destroy and suppress cancer cells. However, it has its drawback, such as high toxicity and limited efficacy in killing the entire tumor, leading to high rates of recurrence. Capecitabine, vinorelbine, cyclophosphamide, and other chemotherapy drugs are examples.
Fourthly, there's the issue of targeted medications. Since the 2000s, these approaches have been thought to be interfering with a process that is necessary for, or supports, tumor development. Nonetheless, it has limitations, particularly in terms of the tumor types that are eligible; high efficiency but short durability leads to high recurrence rates. Imatinib and Lapatinib are two examples of molecular targeted therapy. Parts of them are monoclonal antibodies, for example: Trastuzumab, Rituximab, Alemtuzumab, Bevacizumab, Cetuximab. Some of them are immunoconjugates, such as: Gemtuzumab, Ibritumomab tiuxetan, Tositumomab [1].
Finally, we have immunotherapy. It has been recognized as supporting the immune system's innate ability to recognize and eliminate tumor cells since the 2010s. Immunotherapy has a number of advantages, including the fact that it can be used at any stage of disease, even metastatic tumors; responses are longlasting; it has lower toxicity profiles; and synergistic effects with other treatments.

Cancer Immunotherapy
The fundamental concept of cancer immunotherapy is utilizing the body's immune system to battle cancer. Cancer immunotherapy is classified into two groups, namely active and passive (adoptive). It is called active if the host immune system is stimulated, whereas passive immunotherapy is when there is a transfer of effector molecules or cells (antibody, CTL or Cytotoxic T lymphocytes) to the patient. Both active and passive divided by 2 types are specific and nonspecific, it explained in Table 1.
Over the last three decades, several anticancer immunotherapeutic have been

The Molecular Basis of Cancer Immunotherapy
The

Cancer Immunotherapeutic Approach
One of promising treatments in cancer immunotherapeutic strategies is combined immune checkpoint (ICP) inhibitor treatment and tumor immune microenvironment (TIME)-targeted therapy. TIME appears to play an important role in tumor immune surveillance and immunological evasion, according to elevating evidence. ICP is only one of the many factors that contribute to anti-cancer immunity. Tumors utilize ICPs to defend themselves from immune system attacks. The TIME, on the other hand, is the battleground where the tumor and immune system collide, has an incalculable impact on the result of cancer immunotherapy. Accordingly, combining ICP inhibitors (ICIs) with TIME-targeting therapies is a reasonable strategy for maximizing antitumor immune re-

Cancer Immunosurveillance and Immunoediting
Based on Merriam-Webster online dictionary (https://www.merriam-webster.com/dictionary/immune%20surveillance), immune surveillance is defined as: the monitoring process by which cells of the immune system (such as natural killer cells, cytotoxic T cells, or macrophages) detect and Figure 2. Development and progression of cancer immunotherapeutic strategies. The first-generation of cancer immunotherapy, which included but not definite to immunostimulatory cytokines, aimed to excite the immune system in general in order to encourage a simultaneous antitumor response. The second-generation of cancer immunotherapy, containing but not defined to CAR-T cells, immunogenic cell death (ICD) inducers, and ICP inhibitors, aimed to block peculiar immunosuppressive molecules, induce precise cellular processes, or aim specific tumor cells in order to induce a controllable antitumor response. The third generation of cancer immunotherapy, which included but was not limited to co-targeting of TIME and ICP, aimed to block various aspects of negative immune regulation at the same time in order to mount a safe and effective antitumor response [10].
destroy premalignant or malignant cells in the body. Concisely, immunosurveillance is the processes by which cells of the immune system look for and recognize foreign pathogens in the body. Immunoediting is a term coined to define the energetic interplay between a tumor and its host immune system. This process is constantly modifying the tumor's phenotype [11] [12].
Various experiments showed us that immunity can protect the host from cancer development (i.e., supplies a cancer immunosurveillance function), bolster tumor growth, sometimes by creating more aggressive tumors [13]. There is an arising awareness which cancer immunosurveillance depicts only one stride of a broader process, named cancer immunoediting, that emphasizes the tumor-sculpting actions versus dual host-protective of immune system in cancer [14].
Cancer immunoediting is an energetic process consisting of three phases (three Es): elimination, equilibrium, and escape ( Figure 3). Elimination depicts the classical concept of cancer immunosurveillance. Equilibrium is the period of immunemediated latency after incomplete tumor destruction in the elimination phase.
Escape recognizes the ultimate outgrowth of tumors that have surpassed immunological self-controls of the equilibrium phase [15].
Tumors persist to progress in bodies' cells with flawless immune systems despite immune surveillance.
"Cancer immunoediting" is the method by which the immune system eradicates and embodies malignant disease, and includes three stages, such as: "elimination", "equilibrium" and "escape". Elimination is the pathognomonic of the  . This is pursued by the serenity phase which comprises endless designing of tumor cells and choice of those with diminished immunogenicity, bolstering the result of impervious variants. Cancer cells can invade repose or a slow-cycling condition and endure hidden for continued periods of time. Novel variants with various mutations that escalate resistance to immune pressure arise as long as the equilibrium process, the longest of the three phases that lasts several years [17] [18].

The Hallmarks of Cancer (Can Be) Revisited
The enormous inventory of cancer cell genotypes is a representation of six important changes in cell physiology which systematically govern malignant growth ( Figure 4): apoptosis evasion, sustained angiogenesis, self-sufficiency in growth signals, insensitivity to growth-inhibitory (antigrowth) signals, tissue invasion and metastasis, and unlimited replicative capacity [19].
The six cancer hallmarks-extraordinary and interdependent competences that allow tumor development and metastasis-endure to support a solid foun-T. Ikrar, D. Anurogo dation for comprehension about cancer biology ( Figure 5) [20].
The hallmarks of cancer have been reinterpreted as seven hallmarks, such as: a facilitating microenvironment, immune modulation, modified stress response encouraging overall survival, metabolic rewiring, selective growth and proliferative benefit, vascularization, invasion and metastasis ( Figure 6). Albeit, the concept of the hallmarks implies similarity, it is crucial to understand that cancer is not a single disease, and that tumor types vary in their reliance on-and-off effects of shared pathways. For instance, while vascularization is an essential cancer hallmark, some tumors are weakly vascular and can depend less on it [21] [22].

Nanotechnology Based Cancer Immunotherapy
With the advent of nanotechnology, precise, safer, and more efficient cancer

Immunovaccinomics
The new era of vaccines was started in 1774. At that time, Benjamin Jesty, a farmer, observed a milkmaid who had cowpox, but did not have smallpox. He inoculated his two sons and his wife. This was done 22 years, long before the inoculation process and publication carried out by Edward Jenner in 1798. It was only in the 19th century that the vaccinia virus (poxvirus in mice) proved to be effective in replacing cowpox as a vaccine [26] [27].
Experts first used the smallpox virus as a vaccine candidate until the 1990s.
Vaccine development in that era was still at an empirical stage, with an old perspective, namely: isolation, inactivation, and injection. The fast pace of technology and information encourages the making of vaccines to progress [28].
The progress of the second generation of hepatitis B vaccine is now based on molecular medicine. The next era of vaccines was brought on by the activation of the immune mechanism through the utilization and conjugation of proteins (pneumococcal and meningococcal vaccines), and the HPV vaccine.  . NPs mediated TME modulation for effective immunotherapy. NPs are used to modify the TME by various approaches to enhance antitumor immune response [25].
New perspectives based on immunogenomics and the sophistication of highdimensional genetic and immunological assays facilities, in the form of whole genome sequences, transcriptomic-based mRNA approaches, the latest bioinformatic approaches to study the complexity of immune system mechanisms have made vaccinology enter a new era, namely vaccinomics [29] [30] [31].

Vaccinomics Approach
Vaccinomics is a multifaceted scientific field that studies immunological and biological vaccine responses, as well as the heterogeneity of immune responses. To design logical vaccine approaches, detailed research on the processes underlying host responses to pathogens is combined with high-dimensional epigenetic, genetic, transcriptomic, and proteomic analyses, which culminate in protective immunity. These insights lead to the discovery of new knowledge, which is then applied to the creation of new vaccine candidates after replication and validation, resulting in new insights into biological processes that further scientific knowledge and discovery [32] [33] [34].
Immunogenetics and immunogenomics are integrated with biological systems and immune profiling in vaccinomics. For the production of next generation vaccines and the development of scientists' capabilities in the field of individualized medicine, vaccinomics is focused on the use of high-tech assays (based on omics) and the current bioinformatics approaches. The study was based on genotypic-phenotypic data, supported by comprehensive immune response mechanism milestones that "force" scientists to innovate and uncover the veils behind the interactions between the genes on the heterogeneity of the immune response, as well as the effects of genetic polymorphisms on vaccines. This requires a comprehensive data bank, in the form of genotypic data such as: transcriptomics, gene sequences. Phenotypic data, for both vaccine responders and non-responders, is also needed. Large data is needed by scientists to carry out the process of analysis, observation, replication, interpretation, validation, and implementation.   process. This model uses transcriptomics, proteomics, epitope prediction algorithms, and immune monitoring as "tools".

The Theory of Vaccinology
Second, the immune response network theory. This theory explains immunity as a predictive resultant through the activation and sequential interactions of various genes and various gene pathways. This theory uses "tools" in the form of transcriptomics, proteomics, and pathways analysis.
Third, vaccinomics. This theory discusses a comprehensive study of the immune system, response and mechanism to vaccination so that scientists can understand and predict vaccine-induced immunity, then immediately apply it to the innovation and development of vaccines rationally. This theory uses "tools" in the form of epigenomic, proteomic, immunogenetic/immunogenomic, transcriptomic, immune system monitoring, and computational modeling.

Adversomics
Vaccinomics is an adversomic's "best friend". The two of them are inseparable. The term adversomics emerged in 2009, referring to the understanding of side effects or vaccine reactions based on biological and immunogenomic systems. Simply put, adversomics is a new perspective in vaccine design and safety. Scientists and clinicians urgently need an understanding of basic science, including immunology, molecular biology, and translational, supported by clinical integration to gain a comprehensive understanding of the mechanisms of vaccine side effects in order to design new vaccines that eliminate various pathological events and infection, while avoiding all possible side effects.
Vaccine adversomic studies are an extension of pharmacogenomic studies.
The difference is, if pharmacogenomics studies drugs based on genomic aspects, then adversomics understands vaccines based on a genomic perspective. The methodology of both is relatively the same, although the exact mechanism causing the reaction or side effect of the vaccine is not known until now. Deepening cross-sectional/multidisciplinary involvement to the basics, covering the genetic, molecular, proteomic, adversomic aspects, in particular how the genetic aspects

Immunogenomic Perspectives
In recent years, there has been an explosion of information about innate immunity components and their function in guiding and shaping the adaptive im- Live attenuated vaccines (LAVs) carry native pathogen-associated molecular signals, i.e., viral genetic material that activates the innate immune system via PRRs (pathogen recognition receptors). The LAVs multiply and join the host immune system, where they are picked up by dendritic cells (DCs) or antigenpresenting cells (APCs), which then move to lymphoid organs to demonstrate antigens to T and B lymphocytes. This triggers the same immune responses as natural infections, and it's usually successful after only one dose. These vaccines, Biological systems use a method that is both particular and systematic. It has the potential to not only accelerate the production of new innate immunity regulators, but also to provide a thorough understanding of kinetic regulation at the transcriptional, interprotein, and post-transcriptional levels. All of this knowledge will help to make vaccine discoveries "high impact," by providing molecu-  Figure   8). Establishing vaccines to resist prevailing and impending or prospective pathogens will need us to surmount those obstacles and current progress in genomic sciences may support the solutions that we desire [47]. The high-dimensional assays and advanced genetic, supported by bioinformatics technologies have experienced to a contemporary era of genetic arrangement of vaccines and have contributed real solutions to the impediments presently hindering advancement in this scope (Table 2) [47].  With the latest developments in technology-based multidisciplinary omics, personalized medicine-based vaccines will be better developed, of course still paying attention to safety, efficacy, and (bio) ethical aspects [48] [49].