Hyperthermia (HT), a diverse field with multiple approaches in oncology, is poised to revolutionize cancer treatment. The potential to leverage the therapeutic benefits of heat offers inspiration for improved outcomes for cancer patients, whether as a standalone treatment or in combination with other therapies. The historical origin of hyperthermia, a field traced back to ancient Greek medicine when energy delivery to the body was limited, is a testament to its evolution. The discovery of electromagnetic energy transfers a couple of hundred years ago changed hyperthermia applications. This led to the development of numerous electromagnetic energy transports, including electric and magnetic fields, electromagnetic radiation: direct current, alternating current, radiofrequency (RF), microwave, and visible light. Non-electromagnetic applications such as focused ultrasound and hyperthermic perfusions were also developed. Diverse concepts supported these developments, all with the same goal: to selectively and homogeneously heat up the tumor at higher temperatures than the homeostatic control.

All electromagnetic interactions deliver energy to the biomaterials. The energy could be realized by heat and, consequently, temperature and electron excitation, making chemical reactions. These effects are naturally together because the bioelectromagnetic interactions partly modify compounds’ chemical bonds and structure with electromagnetic forces. One part of the energy absorption heats the target, and the other makes the nonthermal interactions. The two energy components are used in two kinds of hyperthermic therapies in oncology. One direction was Arsene D’Arsonval (1851-1940), a French physician who successfully used nonthermally the electric and magnetic fields for oncotherapy [1] . The direct and alternating currents, mostly nonthermal, are applied with a combination of chemotherapy (electrochemotherapy) [2] in modern medicine. At the same time, the Danish physician Kristian Overgaard (1899-1976) focused on the thermal effect alone [3] . The temperature approach was more straightforward and accessible to control and understand, and so became the mainstream of hyperthermia applications as a return to the ancient wishes with modern technologies. Due to the lack of a complete understanding of bioelectromagnetic processes, controversies were developing around it. Some measurements are misinterpreted, most claims have no data or only some subjective reports, and some results are shown only in individual cases. The wide variety of individual case reports makes it impossible to statistically evaluate those effects, which depends on the treated individuals. However, the debate about the divisive electromagnetic therapies is not useless. It provokes research and points out the physiological importance of electric currents, deriving many modern principles, including the control of the cellular effects [4] and modern neuroscience [5] . Even a general hypothesis of “biologically closed electric circuits” (BCEC) was formed based on the existence of intrinsic electric currents in the body, [6] [7] , which idea is used in the treatment of malignant diseases [8] [9] . The pathological disorders [10] and wounds induce currents [11] . The spontaneous biological charge transfers caused by the tissue-repair process, [12] [13] , and can be used as a noninvasive indicator of wound healing [14] . The biological effects of low-level, non-stationary magnetic fields have been observed [15] and adopted [16] . Among these effects, we may find some resonance character [17] , demonstrating much experimental evidence from the field of ionic cyclotron resonance [18] . Several theoretical explanations of the ion cyclotron resonance have been developed [19] - [24] . The resonance effects are dominantly nonthermal and focus on the molecular excitations and structural changes, inducing desired signal pathways.

Bioelectromagnetic treatments are detached from hyperthermia, while the thermal and nonthermal components are applied in different shares in cancer distortion technical variants. For example, radiotherapy (RT) primarily uses nonthermal molecular breaking in DNA stands, and the thermal effects are negligible. On the contrary, hyperthermia is the opposite; it focuses on thermal energy, when the temperature is the single parameter that measures the dose, and the nonthermal energy is neglected in conventional evaluation. Such an approach to hyperthermia does not differentiate how which technique produces the heat. The exact temperature production is regarded as an identical treatment. However, it becomes increasingly evident that heat production is deeply connected to nonthermal bioelectromagnetic processes. Considering only the heat energy, the thermal homeostatic regulation, the stress reactions, the immunogenic aspects, enzymatic regulations, and many other molecular effects became one-sided, having only thermal dependence. On the other hand, the thermal calories are not equal to the same number of calories from food, inducing nonthermal chemical effects. Life is more chemical-based than thermal, so nonthermal chemistry cannot be neglected when evaluating bioelectromagnetic effects.

Energy absorption produces thermal and nonthermal processes. Thermal effects primarily involve heating tumors to temperatures typically between 39˚C to 45˚C, which may cause direct cytotoxicity, like protein denaturation. Still, it provides a general condition for optimization of the other nonthermal processes. The growing temperature increases the indispensable enzymatic reactions, but the enzymes are blocked over a thermal limit. Also, immune reactions have such thermal limitations. The nonthermal effects can significantly influence the overall efficacy and outcomes of hyperthermia treatments in oncology. The ionizing radiation like radiotherapy (RT) and the chemical interactions of drugs like chemotherapy (ChT), together with the many electromagnetic molecular effects and the immunogenic processes are nonthermal but use thermal conditions for higher efficacy ( Figure 1 ). According to the Arrhenius law, thermal conditions increase sensitivity to radiation, and raising the reaction rate enhances chemotherapy efficacy. The thermal background provides optimal efficacy for the nonthermal effects of ionizing radiation (radiotherapy), chemical reactions (chemotherapy), immune processes (immunotherapy), and electrohyperthermia, which uses the electric field to modify the molecular reactions.

Different hyperthermia techniques may vary in their ability to induce these nonthermal biological effects effectively. Technical differences alter the synergy between thermal and nonthermal energy components.

The thermal and nonthermal processes are synergistically active in all applications, but the ratio of the two components may differ. The complex combination of the thermal and nonthermal effects can alter the physiological and biochemical properties (like blood flow, lymph transport, enzymatic processes, etc.). HT increases the microcirculation [25] - [34] , and enhances the efficacy of the chemotherapies. The enhanced blood flow can improve the delivery of oxygen and ChT drugs to the tumor site [35] - [37] . Further support is that the hot drug is more reactive [38] , providing excellent possibility for synergy, which is even more effective when considering accelerated drug metabolism and gained pharmacokinetic parameters. Furthermore, hyperthermia may activate the G0 phase of cell division, making these states reachable to reaction impacts. These advantages can improve the efficacy of concurrent treatments and reduce the chances of treatment resistance.

Various electromagnetic and technical parameters produce hyperthermia effects, sometimes combined with mechanical actions like ultrasound. The technical variations depend on the various chosen designs ( Figure 2 ). The technical parameters use the wide variability of the electromagnetic processes including the frequency, energy delivery, acting on selected volumes, and selective molecular focusing ability, the fiend could be formed in invasive form, and depends on the energy source, the energy coupling to the target and at the end the combined (complementary) applications with other treatments concomitantly or concomitantly next to each other.

Techniques differ in how the physiological changes can be manipulated effectively and how to improve treatment outcomes. The methods differ in activating the blood vessel permeability in tumors, which can enhance the delivery of chemotherapy drugs or oxygen to the tumor site. The nonthermal effects of various hyperthermia techniques involve a complex interplay of molecular excitations and biological responses triggered by cellular stress responses to elevated temperatures. These responses encompass a range of molecular pathways and signaling mechanisms that influence cell survival. The hyperthermia technique also varies by modulation of the immune response, potentially enhancing immune recognition and attacking cancer cells, increasing the therapeutic outcomes in oncology.

The technical solution may vary the efficacy [39] , modify the reaction rates measured by the Arrhenius plot [40] , and develop different amounts of HSPs [41] , different cell destruction [42] [43] , different immune activity [44] [45] , modifying the preclinical [46] and clinical results [47] . Various techniques differ in enhancing the synergistic effects of other cancer treatments, such as RT or ChT, by optimizing nonthermal mechanisms that may improve patient outcomes. The consequence of the variations appears in the essential differences between the characterization of the methods in Figure 3 .

Understanding how thermal and nonthermal effects interact allows us to optimize basic treatment parameters such as temperature, duration of treatment, and integration with other therapies. Technical optimization maximizes therapeutic efficacy while minimizing adverse effects on healthy tissues. The optimum of the multivariant process is a complicated task, which is the primary intention for all hyperthermic designs. The optimum is a Nash equilibrium [48] . In this state, no further change of the technical parameters produces higher efficacy, and the contradictory interactions compensate each other in a balance. The equilibrium could be lost by changes in the conditions (different individuals, tumor stage and change, increasing temperature, etc.), which needs to repeat the optimizing process.

The differences in results between hyperthermia techniques can arise due to several other factors:

1) Different techniques may heat tumors to the same average temperature, but the distribution of heat within the tumor and penetration depth can vary. Some methods may be better at uniformly heating the tumor throughout its volume, a factor that can significantly influence treatment outcomes.

2) Variations in how well different techniques achieve and maintain the target temperature can affect treatment efficacy and safety.

3) The way heat is transferred to tissues can vary between techniques. Factors such as tissue perfusion (blood flow) and the thermal properties of tissues can impact how effectively the desired temperature is reached and maintained within the tumor.

4) Hyperthermia is often used in combination with other cancer treatments. The synergy between hyperthermia and these treatments may differ depending on the specific technique, influencing overall treatment outcomes.

5) Variability in patient anatomy and tumor characteristics can also interact differently with various hyperthermia techniques, affecting individual treatment responses.

The pivotal difference between the applied techniques is the ratio of thermal and nonthermal effects. The default effect is thermal. The nonthermal impact is a complementary additive to the thermal one. The nonthermal effects are induced nonionizing in the tumor microenvironment (TME) by the electric field. The complementary synergy of these effects works like the synergic addition of nonthermal ionizing radiation (radiotherapy) to the thermal impact alone, which is a well-proven combination [49] - [51] . The thermal effect and chemotherapy combination are similar to thermal and nonthermal amalgamation. The ChT focuses on chemical reactions, which are nonthermal, but the thermal conditions may accelerate the reaction rate and the transport of the chemical drugs [52] - [54] .

The nonthermal effects are a larger category than hyperthermia. Ionizing radiation, nonionizing radiation, electromagnetic fields, and drug-induced chemo changes are all nonthermal ( Figure 4 ). The thermal effects promote nonthermal processes, which could change the molecular bonds and make signal excitations by nonionizing energy as HT does. It does not have enough energy to ionize atoms or break chemical bonds. When the energy is as high as in the ionizing range, like in radiotherapy (RT), it breaks the molecular bonds. The synergy of these nonthermal effects works in thermo-radio-chemotherapy complementary applications. Thermally-induced nonthermal effects can stimulate anti-tumor immune responses by promoting antigen presentation, activating dendritic cells, and enhancing T-cell function. Changes in the TME, including increased infiltration of immune cells and modulation of immune checkpoints, can contribute to improved anti-tumor immunity.

The essential biological differences between the electromagnetic hyperthermia techniques include numerous molecular and physiological changes ( Figure 5 ). The consequence of the technical differences is the massive variation of the effects achieved with the applied method.

The mEHT fits the latest trends in oncotherapy development [89] [90] . It is selective, safe and immunogenic.

The perspectives of hyperthermia, especially the modulated electrohyperthermia, have multiple possible ways for future realization.

1) Hyperthermic therapies must increase their focus on the target, avoid unwanted hot spots in healthy tissues, and limit heat spreading by natural heat conditions. The mEHT, with its molecular selectivity on the membrane rafts of malignant cells, optimizes the selectivity of energy absorption.

2) Hyperthermia must harmonize thermal and nonthermal processes to choose the best signal pathways to destroy the tumor. The mEHT optimizes the molecular actions and signals excitations with a synergy of the thermal and nonthermal processes.

3) The rapid development of immuno-oncology affects all modern oncology treatments. Hyperthermia must fit this new trend. The mEHT, which induces immunogenic cell death, induces immunogenic effects and could be well harmonized with other immunotherapies.