The combination therapy of magnetic hyperthermia at 46°C with the immunomodulators (glycyrrhizin+CpG+anti-PD-1+anti-CTLA-4) achieved complete tumor regression in 80% of growing 5-mm B16-F10 tumors in C57BL/6 mice. Complete tumor regression was also observed in mouse CT26 colon carcinoma even at 43°C, and strong suppression of CT26 tumor growth was maintained for 30 days. The authors note that in situ vaccination caused by magnetic hyperthermia alone is often insufficient to induce complete regression of poorly immunogenic tumors surrounded by an immunosuppressive microenvironment, hence the need for combination with immunomodulators.

William Coley developed a treatment known as Coley’s toxin, which combined heat-killed Streptococcus bacteria with Serratia marcescens. By 1893, he treated 10 patients with encouraging results, leading to further documentation of 80 more cases by 1916 and publishing over 150 papers. Her research revealed that nearly 500 of these cases exhibited near-complete tumor regression, underscoring the potential efficacy of Coley’s therapeutic approach. Coley compiled evidence from approximately 47 cases documenting the tumor-shrinking effects of infections, further motivating him to understand this phenomenon for cancer treatment. Coley's toxins were effective but lacked evidence of correlation to clinical success and cancer remission, and inconsistencies in results and lack of standardized formulations contributed to their eventual decline in use.

The observation, that cancer patients who experienced a feverish period after surgery survived significantly longer than patients without fever, and the fact that spontaneous tumor remission was observed mostly after a fever period, was the rationale for the artificial induction of fever (“fever therapy”). Analysis of the literature reveals leukemia with ≥22% being the magnitude of cases where infection was associated with remission, followed by bone and connective tissue cancers with ≥15%, melanoma with ≥11% and lymphoma with ≥7%. Finally, in a recent monograph on spontaneous remissions of malignant melanoma Maurer and Kölmel list 21 cases of the world literature, where febrile infections have been associated with spontaneous regression of metastatic melanoma; these authors state further “the connection of febrile infection and tumor regression is the most frequent association found in the literature”.

Frequent and well-known associations of spontaneous cancer regression involve concomitant infection, febrile episodes and hormonal influences. Fever is another well-documented correlating factor with spontaneous regression of cancer. According to a trial by Nauts and McLaren, when the ‘Coley’s toxin’ preparation was used in the treatment of surgically inoperable cancers, the efficacy was higher in patients who suffered from interim high fevers (>38 °C). It has been postulated that cancer cells are less resistant to increased body temperature than normal cells. Spontaneous regression of cancer is an extremely rare occurrence, especially in pancreatic carcinomas.

Hyperthermia is a type of treatment in which body tissue is heated to as high as 113 °F (about 45 °C) to help damage and kill cancer cells with little or no harm to normal tissue. Hyperthermia is almost always used with other forms of cancer treatment. Many clinical trials have shown that hyperthermia, when used with treatments such as radiation therapy and chemotherapy, helps shrink tumors and may make it easier for them to kill cancer cells, but it is not clear if it helps people live longer.

In 1891, William Coley noticed several clinical cases of spontaneous regression and disappearance of tumors in patients following infection. He conceived the idea of injecting cancer patients with a Streptococcal concoction to induce similar infections, and these toxins, widely referred to as Coley's toxins, were extensively used for the next 30 years to treat several inoperable sarcoma cases. Despite obtaining excellent initial responses, these toxins faced enormous criticisms and disapproval by many leading surgeons at that time, primarily because of the inconsistencies. From the year 1962, the use of Coley's toxin, as a therapeutic, was banned by the Food and Drug Administration USA. Several years later, Murray Shear and his colleagues unveiled that bacterial lipopolysaccharide is the active component present in the Streptococcal concoction, leading to tumor regression.

Accumulating evidence indicates that survival benefits are accorded to individuals who achieve an increase in body temperature (i.e. fever) following infection. Moreover, in the mid-1800s, physicians reported significant tumor regression in some cancer patients who experienced high fevers during natural infection by erysipelas, the same bacterial strain that Coley used to inoculate his patients. There is increasing evidence that exposure of tumor cells to hyperthermia enhances sensitivity to immune cell recognition and killing, for example by enhancing expression of heat shock proteins on the tumor cell surface and activating NK cells.

A large fraction of spontaneous regressions and remissions described in the literature was preceded by a hefty feverish infection. I will collect evidence that high fever was a time correlate in many cases of spontaneous regression, and will argue that fever might play a dominant role in helping the immune system to overcome tolerance. Rohdenburg (1918) stated, ‘The greatest number of spontaneous regressions have occurred following incomplete surgical removal of the tumour, next in order of frequency during some acute febrile process…’. Diamond and Luhby (1951) reported 26 spontaneous remissions in a cohort of 300 cases of childhood leukaemia, 21/26 (80%) were accompanied by infection. In a collection of 68 well-documented cases of regression from melanoma, Maurer and Koelmel (1998) found 21 cases with febrile infection preceding regression (31%).

He found a smattering of reports in which patients who accidentally contracted erysipelas enjoyed stunning cancer remissions. Altogether, Coley found 47 cases in the literature documenting infection-associated tumor remissions. Convinced that a serious infection could elicit an anti-cancer effect, "I determined to try inoculations [of bacteria] in the first suitable case." Treatment success correlated with the length of treatment and the magnitude of the fever induced by the toxins. The longest remissions, including many cures, were associated with repeated long-term toxin treatment, sometimes lasting 3–4 years. Nauts’s extensive analysis showed that her father had achieved an impressive success rate in treating certain tumors, with more than 500 of approximately 1,000 cases showing near-complete tumor regression.

These effects contribute to the transformation of immunologically “cold” tumors into “hot” tumors, making them more susceptible to immune-mediated destruction. Furthermore, hyperthermia can amplify the efficacy of immune checkpoint inhibitors by improving immune cell infiltration, inducing damage-associated molecular pattern release, and enhancing antigen presentation. Preclinical and clinical studies support the combination of fever-range hyperthermia with immune checkpoint inhibitors, demonstrating improved outcomes in otherwise resistant tumors, and Yu et al. reported that hyperthermia-induced immune activation might influence long-term survival in rectal cancer patients.

Experimental and clinical evidence shows that mild hyperthermia improves tumor perfusion and oxygenation, enhances the expression of heat shock proteins, promotes antigen presentation and dendritic cell maturation, facilitates lymphocyte trafficking, and triggers the release of immunogenic and danger-associated signals that amplify antitumor immunity. Mathematical analysis incorporating temperature-dependent modulation suggests that moderate hyperthermia reduces tumor proliferation and enhances immune effector recruitment and cytotoxic activity, thereby increasing the probability of tumor control. These antiproliferative effects, while not directly cytotoxic at moderate temperatures, contribute to slowing tumor growth and creating a therapeutic window for immunomodulation or combination therapy.

Meyerding used the toxins in conjunction with surgery for patients with bone cancer, achieving survival rates far higher than with surgery alone. Helen Coley Nauts presented abundant evidence that her father’s method had indeed worked in a significant number of patients. “Those who have scrutinized Coley’s results have little doubt that these bacterial toxins were highly effective in some cases,” wrote Lloyd J. Old, MD, associate director of Memorial Sloan Kettering. Patients in modern phase I trials received subcutaneous injections of Coley’s toxins twice a week until fever was induced, and then for four additional doses. The toxins were effective at inducing fever and robust surges in cytokines; one patient with metastatic bladder cancer had a clear clinical response, experiencing a 50% reduction in his cancer that correlated with elevated levels of cytokines. However, in a controlled study sponsored by the National Cancer Institute, the initial survival advantage of the Coley’s toxins group disappeared as the curves eventually merged and the study was stopped.

Evidence now exists that show that raising the body temperature can favor the induction of an immune response against tumors. As reviewed above, fever-range temperature can modulate the activities of immune cells, including antigen-presenting cells, T cells and NK cells. These data support the concept that hyperthermia and fever-range temperatures can regulate immune responses that may be directed against tumor cells.

We report two cases of remission from cancer observed shortly after an acute, febrile infection: one in the preleucemic condition myelodysplastic syndrome (MDS) and one in non-Hodgkin lymphoma (NHL). In both cases, the fever was accompanied by an elevation of C-reactive protein and several cytokines. These case reports support the concept that acute infection with high fever might, in rare cases, trigger regression in malignant disease, possibly through activation of anti-tumour immune mechanisms.

There is considerable circumstantial evidence that the immune system is involved in the tumor regression and host cure that may follow curative local tumor heating in animals. Reports in allogeneic and syngeneic animal systems show that successful local tumor heating can lead to regression of tumor at other anatomical sites (the so-called abscopal anti-tumor response), but there is no definitive evidence for stimulation of an effective anti-tumor response in humans following tumor heating and no indication that total-body heating (fever-range) cures cancer in man. The data indicate that an intact immune system is necessary for tumor regression after curative heating, but there is little evidence that the host response involves specific anti-tumor-directed cells.

Dr. Coley’s efforts were inspired by his observation of a link between spontaneous infections and cancer regression, sometimes of very advanced and metastatic cases. Helen spent several years poring over 15,000 of her father’s letters, compiling information on more than 1,000 cancer patients who were treated with his approach, and another 450 cancer patients who had natural bacterial infections. Her conclusion was that the treatment, dubbed Coley’s Mixed Bacterial Toxins or Coley’s Toxins, did work in many instances, but she also discovered that there had been several different formulations of the toxins in use, not all of which were effective, resulting in inconsistent and often unreproducible results. By studying survival rates following surgery alone and surgery combined with toxins in operable cancer of various types, she found that one could expect a far higher percentage of long-term survival than from the very best surgical procedures, with or without radiation. She emphasized that bacterial infections and toxins seemed to operate through an indirect effect on the body’s natural powers of resistance, stimulating what was then called the reticulo-endothelial system (early term for the immune system).

We have reviewed sixteen case reports of COVID-19 disease with spontaneous cancer reduction or progression. Fourteen cases of remission or regression and two cases of reduced progression were identified. In several reports, spontaneous cancer remission occurred after COVID-19 infection without additional anti-cancer treatment, suggesting that acute infection and the associated inflammatory and febrile response may act as a trigger in rare cases. However, these observations are based on isolated case reports, and the mechanisms and causal relationships remain unclear.

Up to 40 °C, neutrophil infiltration is increased in tumors, causing tumor regression due to hyperthermia-mediated antitumor immune effects. At temperatures above 42–43 °C, pro-apoptotic and necrotic mechanisms dominate, directly damaging tumor cells. The review notes that while induced hyperthermia can mediate tumor regression in preclinical models, in clinical settings hyperthermia is usually employed as an adjuvant to radiotherapy or chemotherapy rather than as a stand-alone curative treatment.

The results of our study support the hypothesis that during their lifetime cancer patients experience less fever during infection than healthy controls. Cancer patients reported a lower incidence of fever during illness than controls. The percentage of cancer patients and controls who reported no fever during infections was 83.10% and 56.97%, respectively. Similarly, 16.90% of cancer patients and 43.03% of controls reported always experiencing fever during infections. These findings are in line with epidemiological data suggesting that a personal history of feverish infections may be associated with a reduced likelihood of developing cancer.

In 1890, Coley operated upon a 17-year-old female patient with sarcoma who succumbed to the aggressive disease despite radical treatment. Following this, he identified historical cases where cancer regression appeared after erysipelas infection and went on to develop a heat-killed bacterial vaccine, later called Coley’s toxin, to reproduce this effect. The article traces the path from Coley’s toxin to the first approved therapeutic cancer vaccine, noting that while Coley’s preparations were not standardized and yielded variable clinical outcomes, they played a pioneering role in demonstrating that immune stimulation by infection-associated fever and inflammation could contribute to tumor regression and inspired later, more controlled immunotherapies.

We report two cases of remission from cancer observed shortly after an acute, febrile infection: one in the preleukemic condition myelodysplastic syndrome (MDS) and one in advanced endometrial carcinoma. During a bacterial infection, pathogen-associated molecular patterns are present in the tumor microenvironment and proinflammatory conditions arise that may break immune tolerance against the tumor, providing a possible explanation for regression following fever and acute infection.

Acute infections (mild acute inflammatory responses) may cause a spontaneous remission of cancer as reported by many case reports in the medical literature. Complete spontaneous remission of diffuse large B-cell lymphoma of the maxillary sinus after concurrent infection: according to the authors the patient had pneumonia and Clostridium difficile toxin with fever; a short while afterward the patient had a remission of lymphoma without any signs or symptoms. Spontaneous complete remission in a patient with acute myeloid leukemia and severe sepsis is another example. The fever occurring prior to the spontaneous remission of cancer is significant. When Coley's toxin (bacteria that was not live) was used, those instances in which a fever occurred were more likely to be followed with a remission of cancer.

Systemic lidocaine administration enhanced hyperthermia-induced tumor regression in a murine model. The serum levels of lidocaine necessary to achieve tumor regression were within the therapeutic range for the control of arrhythmia in humans. Several treatment protocols using combinations of hyperthermia and systemic lidocaine resulted in significant regression of established tumors, suggesting that pharmacologic modulation can increase the effectiveness of hyperthermia-induced tumor damage.

Spontaneous regression or remission is the partial or complete disappearance of an untreated malignant tumor or a tumor treated with a therapy considered inadequate to exert significant influence. About 1,000 case studies in the medical literature during the past century detail spontaneous regression from cancer. A prior fever was recorded in 25 to 80 percent of documented cases of spontaneous regression of cancer; for example, in a cohort of 300 cases of childhood leukemia, 80 percent of 26 spontaneous remissions were accompanied by infection, and in another series 28 percent of 224 regressions were preceded by infection or persistent temperature elevation.

Hybrids-mediated magnetic hyperthermia treatment promotes tumor regression in vivo via destroying mitochondrial function in tumor cells. In mouse models, injectable magnetic hydrogel subjected to an alternating magnetic field induced localized heating, leading to multi-programmed cell death and marked reduction of tumor volume compared with controls. The study supports the concept that targeted, controllable hyperthermia can induce regression of solid tumors in preclinical models, primarily through direct cytotoxic effects rather than systemic fever.

Although the link between overwhelming bacterial infections and seemingly spontaneous regression of cancer had already been suspected, Coley was the first to describe the process of activating a patient’s immune system with bacterial toxins to mimic sepsis induced by live bacteria to treat cancer. Coley’s original idea was based on his observation of one patient with resistant incurable sarcoma of the skin, which regressed completely following a severe infection with streptococcus bacteria. He designed his toxin using a sterile mixture of different types of bacteria (Streptococcus pyogenes and Serratia marcescens) to induce similar therapeutic effects using a safe toxin. This mixture, known as Coley’s toxins, caused fever and shivering similar to true infection, and he noted that some patients responded with complete tumor regression. The article argues that this 120-year-old observation—that an induced febrile immune response could sometimes be associated with cancer regression—was largely ignored in favor of later chemotherapeutic approaches.

Despite examples of efficacy, “Coley’s Toxins” were eventually displaced by radiation therapy. Dr. Coley’s colleagues, especially his supervisor at Memorial Hospital, did not believe his claims and were concerned about the unpredictable, sometimes severe fevers and reactions induced by the bacterial injections. The use of these fever-inducing bacterial toxins to treat cancer fell out of favor as more controllable modalities, such as radiation and later chemotherapy, became standard of care, even though historical case reports documented tumor regression following infection-associated fevers in some patients.

In a patient with multiple myeloma, fever episodes were temporally associated with spontaneous remission. However, after episodes of fever, most of her tumours disappeared, and the remaining ones stabilized. The frequency of spontaneous remission of multiple myeloma is estimated at 1 in 400 patients. The authors note that spontaneous remission in cancer remains an exceptional event, often reported as isolated case reports, and that causal mechanisms, including the role of fever, are still speculative.

In 1893, surgeon William Coley began treating cancer patients with a mixture of heat-killed bacteria (“Coley’s toxins”) after noticing that patients with cancer sometimes experienced tumor regression following severe infections accompanied by high fever. This approach, inducing fever and inflammation through controlled bacterial exposure, is recognized by Memorial Sloan Kettering as an early form of immunotherapy that attempted to harness the body’s own immune response to attack cancer. The timeline notes that although Coley’s fever-inducing toxin therapy produced some remarkable remissions, it lacked modern clinical trial validation and standardization, and thus did not become an accepted mainstream treatment.

Spontaneous remission of cancer occurs when cancer shrinks or disappears without curative treatment. Many case reports indicate patients experienced spontaneous remission after a serious infection, and those infections often caused high fevers. Researchers have linked several factors to spontaneous remission, including fever with infection or sepsis, hormonal changes, and immune system activation. However, spontaneous cancer remission is quite rare—only about 12–24 cases appear in the medical literature each year—and there is no established medical protocol that uses fever alone as a cancer cure.

Hyperthermia (HT) is a proven treatment that holds Level 1A evidence (based on Phase III randomized trials and meta-analyses) for major tumor entities as an adjunct to radiotherapy and chemotherapy. Clinical studies summarized here report that regional hyperthermia in combination with radiochemotherapy significantly improves local tumor control and, in some indications, overall survival compared to radiochemotherapy alone. The authors emphasize that oncologic hyperthermia is not used as monotherapy but integrated into multimodal treatment concepts to achieve tumor regression and better outcomes.

Infectious fever makes our bodies more resilient to cancer by increasing and strengthening a particular group of cells in the immune system, gamma-delta T cells. For decades, studies have suggested that there is a link between history of infectious fever and lower risk of cancer—but as yet, there is no direct proof of cause. The authors argue that repeated fever responses to acute infection increase the ability of gamma-delta T cells to spot abnormal cells and cultivate environments that destroy them, but they stress that at present this is just a theory.

Spontaneous remission of cancer is defined as the partial or complete disappearance of a malignant tumour without adequate medical treatment. Case reports have documented spontaneous remissions in various cancers, including lung, melanoma, neuroblastoma, and lymphomas. Proposed mechanisms include immune system activation after infections and fevers, hormonal influences, and tumour-related factors. On the whole, spontaneous remission is considered a rare phenomenon, and researchers caution that these cases should not be interpreted as evidence that fever or infection is a reliable therapeutic strategy for cancer.

Historical cancer therapies such as "Coley’s toxin" deliberately induced high fevers in cancer patients using bacterial extracts, and some remissions were reported in association with these fever episodes. Modern reviews of spontaneous cancer regression emphasize that such remissions are extremely rare and typically occur after acute infections or strong immune activation, not after ordinary mild fever. Contemporary oncology does not consider fever itself a proven curative treatment for cancer; instead, fever is viewed as a possible trigger or correlate of immune responses that in rare cases may contribute to tumour regression.

He observed that several sarcoma patients, and especially one patient suffering from recurrent inoperable sarcoma of the neck, experienced tumor remission after developing erysipelas, a superficial streptococcal infection of the skin accompanied by high fever. Fever therapy by Coley's bacterial vaccine provokes a powerful reaction of the immune system, with reported antitumor effects including induction of interferon, augmentation of natural killer cell activity, activation of macrophages, and induction of serum factors that cause necrosis of tumors. The Issels clinic claims that tumors may swell slightly during the fever treatment and sometimes, a few days thereafter, patients notice a reduction in tumor size, but these observations come from an alternative therapy center rather than controlled trials.