Cancer has existed for millennia, predating humanity itself, and has been a significant challenge since our earliest days [18–20]. Key milestones in cancer understanding and management over time are highlighted in Table 1 [18,21–83]. Early insights into tumor immunity stem from ancient observations that hinted at the immune system’s role in cancer. For instance, spontaneous tumor regression, sometimes observed following infection and high fever, was noted as far back as ancient Egypt, 3,000 years ago [84–86]. These early observations, although anecdotal, laid the groundwork for later scientific inquiry into the interaction between the immune system and cancer.

A crucial figure in ancient cancer theory was the Greek physician Galen, who lived around 2,000 years ago [87]. He speculated on the role of inflammation in cancer, observing that tumors often arose in regions of previous injury or inflammation. His hypothesis that chronic inflammation could lead to cancer growth, though limited by the medical knowledge of his era, laid an early foundation for exploring the links between the immune system and cancer [85,87,88]. Galen’s term “oncos” for tumors persists in modern terminology, and his theory of “black bile” causing incurable cancers, while “yellow bile” indicated curable tumors, reflects an early attempt to categorize cancer based on perceived pathology [25].

By the 19th century, scientific understanding began to evolve. In 1828, French surgeon Jean Nicholas Marjolin noted the development of squamous cell carcinoma in burn scars, introducing the idea that chronic irritation could lead to cancer [33,36,89]. English surgeon Caesar Hawkins corroborated this observation in 1833 by noting cases of skin cancer arising near old burn wounds [35,36]. This era’s most significant contribution came from Rudolf Virchow, who in the late 19th century identified leukocytes within tumor tissues. He proposed the groundbreaking theory that tumors could originate from areas of chronic inflammation, advancing the link between inflammation and cancer significantly [39,40,90].

The idea that infections could influence cancer regression was further explored by German physicians Fehleisen and Busch in the 19th century. Both independently observed tumor regressions in cancer patients following erysipelas (a Streptococcus pyogenes infection) [91–94]. While initial attempts to harness this for systematic cancer treatment had mixed success, Fehleisen succeeded in isolating the bacterial strain responsible for both the infection and tumor reduction, marking a milestone in immunotherapy [94–96]. This work would later inspire William Bradley Coley’s famous experiments with bacterial toxins, laying the foundation for modern cancer immunotherapy in the late 19th and early 20th centuries [3,43,85].

In the early 20th century, Paul Ehrlich introduced the concept of “immune surveillance,” suggesting that the immune system continuously monitors the body for abnormal cells, including cancerous ones [97–99]. This hypothesis marked a major shift in understanding the immune system’s role in cancer prevention. Although experimental tools at the time were insufficient to verify the theory, Ehrlich’s ideas laid the groundwork for future research on how immune dysfunction could contribute to cancer progression. Later, Lewis Thomas proposed that the immune system detects newly developing tumors through the recognition of tumor-specific neoantigens expressed on tumor cells, mirroring the rejection process observed in tissue grafts. This mechanism aids in maintaining tissue balance in complex multicellular organisms [100]. The initial clear demonstration of the immune system’s specific capability to elicit a response occurred in 1943. Gross achieved this by immunizing C3H mice, bred through continuous sibling mating for over 20 years, against a sarcoma via intradermal injection. Subsequent research has explored and confirmed these aspects, demonstrating the active role of the immune system in identifying and eliminating cancerous cells through various immune mechanisms, including cytotoxic T cells, natural killer (NK) cells, and other components of the immune response [101,102].

The mid-20th century saw a deeper understanding of immune mechanisms. Moritz Wilhelm Hugo Ribbert, a pathologist from Zurich, suggested that chronic inflammation and mechanical irritation could lead to epithelial and connective tissue proliferation, predisposing tissues to cancer [45,91]. Research by George Klein later expanded this understanding, revealing that the immune system could distinguish and eliminate tumor cells. Klein’s work on major histocompatibility complex (MHC) antigens and immune responses to tumors played a pivotal role in tumor immunology and provided key insights into how tumors evade immune detection [103–106]. This era also saw the development of transplantable tumor models, which allowed scientists to study immune responses to cancer systematically, laying the foundation for modern immunotherapy [107–115].

In the latter part of the 20th century, cytokine therapy emerged as a promising cancer treatment. Alick Isaacs and Jean Lindenmann’s discovery of interferons in 1957 and subsequent discoveries of IL-1 and IL-2 marked major milestones [116–122]. Interferon-based therapies, particularly interferon-α, became the first cytokine therapy approved by the Food and Drug Administration (FDA) for treating hairy cell leukemia in 1986, opening the door to cytokine-based cancer treatments [123–125]. Similarly, IL-2 therapy gained approval for treating metastatic renal cell carcinoma and melanoma in the 1990s, further solidifying the role of cytokines in cancer immunotherapy [126].

In the mid-to-late 20th century, groundbreaking advancements in biotechnology emerged with the advent of hybridoma technology, pioneered by Georges Köhler and César Milstein. For their revolutionary contributions, they received the Nobel Prize in 1984 [127–129]. This technique facilitated the production of monoclonal antibodies, marking a significant milestone in biomedical research and therapeutic development [130]. The origins of antibody understanding, however, trace back to Behring and Shibasaburo Kitasato’s work in 1890, where they identified “antitoxins” in blood, now understood as antibodies. These antibodies neutralized bacterial toxins, such as those causing diphtheria and tetanus, laying the foundation for our understanding of antibody-mediated immunity [131,132].

Subsequent research in the 1930s by Michael Heidelberger and Oswald Avery further elucidated the chemical nature of antibodies and their antigen-specific binding capacity, providing key insights into the molecular basis of the immune response [133,134]. Astrid Fagraeus’s work in the late 1940s demonstrated that plasma cells produce antibodies, solidifying our understanding of how the adaptive immune system responds to antigens [135]. In the 1960s, Sir Gustav Nossal and Joshua Lederberg provided strong evidence for the clonal selection theory, initially proposed by Frank Macfarlane Burnet and David W. Talmage. Their experiments demonstrated that each B cell clone produces antibodies of a single specificity, underpinning the principles of monoclonal antibody technology [136,137].

Monoclonal antibodies, characterized by their specificity to a single epitope, became a focal point of cancer research for their potential in targeted therapy. The approval of rituximab, a monoclonal antibody targeting the CD20 antigen for lymphoma treatment in 1997, marked a watershed moment in medical history [138–140]. Today, monoclonal antibodies are integral to precision medicine, offering targeted therapeutic options across a range of malignancies.

This milestone paved the way for the exploration of novel antibody-based treatments for various malignancies and spurred further research and development efforts, leading to the discovery and approval of additional monoclonal antibody therapies for different types of cancer [140]. Hybridoma technology and monoclonal antibodies continue to play a crucial role in modern medicine, offering targeted and personalized treatment options for patients battling cancer and other diseases [128,141].

In the 1990s, the discovery of immune checkpoints like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) transformed the landscape of cancer immunotherapy. James P. Allison and Tasuku Honjo’s groundbreaking research led to the development of immune checkpoint inhibitors, which block the inhibitory signals that prevent the immune system from attacking cancer cells [142–147]. Drugs like ipilimumab and pembrolizumab have since revolutionized cancer treatment, particularly for previously untreatable malignancies.

In the 2010s, adoptive cell transfer therapies, including tumor-infiltrating lymphocyte and chimeric antigen receptor (CAR) T-cell therapies, brought even more innovative approaches to immunotherapy [148,149]. CAR-T cell therapy, in particular, demonstrated remarkable success in treating hematologic cancers by genetically engineering T-cells to target specific cancer antigens [70,150,151]. The first CAR-T therapy approval in 2017 marked a pivotal moment in cancer treatment, offering a new avenue for targeting and eliminating cancer cells with precision [152–157].

Throughout the history of cancer immunology, the evolving understanding of the immune system’s role in cancer progression and treatment has paved the way for the development of increasingly sophisticated therapies, transforming the field of oncology and offering new hope for patients worldwide. Preclinical, and early clinical studies have shown promising results for both CAR-M and CAR-NK cells [157–163].

Over the last five decades, there has been a concentrated effort to develop cancer vaccines, yielding only modest achievements [164,165]. Yet, recent progress in genetics, molecular biology, biochemistry, and immunology has reignited enthusiasm for these immunotherapies, leading to the emergence of promising candidates for cancer, since the 2000s the development of cancer vaccines, encompassing both therapeutic and preventive approaches, has represented a significant frontier in cancer immunotherapy [165,166]. Furthermore, ongoing efforts are focused on combining cancer vaccines with other immunotherapies, such as checkpoint inhibitors, to enhance anti-tumor immune responses and improve treatment outcomes [167,168]. While significant challenges remain, including issues related to vaccine efficacy, safety, and patient selection, the development of cancer vaccines holds great promise for the future of cancer treatment and prevention [169]. Continued research and clinical trials are critical for realizing the full potential of cancer vaccines in improving patient outcomes and reducing the global burden of cancer.

Fig. 1 presents the chronological progression of significant discoveries and breakthroughs in immunotherapy. It began in 1891 with Coley’s toxin, an early attempt at using bacterial toxins to treat cancer. In 1957, Burnet’s immunosurveillance theory was proposed, suggesting that the immune system plays a role in recognizing and destroying cancer cells. In 1975, hybridoma technology was developed, enabling the mass production of monoclonal antibodies, revolutionizing targeted cancer therapies.

The timeline continues with the discovery of crucial immune checkpoints: CTLA-4 in 1995, which led to the development of immune checkpoint inhibitors, and PD-1 in 1992, another key checkpoint protein that plays a role in preventing the immune system from attacking normal cells. These discoveries paved the way for immunotherapy drugs like pembrolizumab, which received FDA approval in 2014 for the treatment of melanoma, marking a major milestone in immune checkpoint blockade therapy.

In 2012, the Nobel Prize for the discovery of CRISPR was awarded, revolutionizing gene editing technology with applications in cancer research. This was followed by the FDA approval of CAR-T cell therapy in 2017, a breakthrough in personalized cancer immunotherapy targeting blood cancers. The timeline concludes with the FDA approval of Opdualag in 2022, a novel combination of immune checkpoint inhibitors (nivolumab and relatlimab), signifying continued advancements in immunotherapy for treating melanoma.

The quest to understand tumor immunogenicity in the context of cancer therapy has been a profound and multifaceted journey, intertwining decades of scientific research, clinical observations, and technological progress [170]. This narrative unfolds against a backdrop of perseverance, skepticism, and ultimately, groundbreaking discoveries that have revolutionized the field of oncology [171]. Tumor immunogenicity is determined by the tumor cells themselves and is also influenced by factors within the tumor microenvironment (TME), including the activity of antigen-presenting cells like dendritic cells (DCs) [172]. The primary factors that determine tumor immunogenicity are the presence of tumor-specific antigens and the efficiency of antigen processing and presentation [173].

The foundation of understanding tumor immunogenicity in cancer therapy can be traced back to the pioneering efforts of Dr. William B. Coley (1862–1936), a bone sarcoma surgeon, in the late 19th century, around 1891 [43]. Dr. Coley’s empirical observations of some cancer patients experiencing spontaneous tumor regression following erysipelas, a streptococcal skin infection, served as the catalyst for the recognition of the immune system’s potential in combating cancer. He hypothesized that the immune response triggered by the infection might also be attacking the cancer cells [174,175]. Coley extensively reviewed medical records, case reports, and literature available to him in the late nineteenth century. He found numerous instances of potentially incurable cancers undergoing spontaneous remission following acute bacterial infections. This provided further evidence supporting the potential role of the immune system in fighting cancer. Building upon his observations and understanding, Coley began experimenting at Memorial Sloan-Kettering Cancer Center in New York, by injecting a mixture of heat-killed streptococcal bacteria and another organism, now known as Serratia marcescens (Coley’s toxin), directly into tumors (mostly bone and soft-tissue sarcomas), achieving a cure rate of over 10% [43,174–176]. By doing so, he aimed to stimulate the immune system’s response against cancer cells. This approach laid the foundation for what can be considered the first immune-based treatment for cancer. In 1891, Coley made his initial endeavor to utilize the immune system for treating bone cancer [43,86]. Coley’s experiments encountered skepticism in his era because of the unclear understanding of their mechanisms of action and concerns regarding the potential risks of infection. Significant criticisms emerged within the scientific community because many physicians did not believe his results, particularly highlighted in the Journal of the American Medical Association (JAMA) in 1894, where a statement was issued condemning the use of his toxins. The part of statement issued in JAMA read as “There is no longer much question of the entire failure of the toxin injections, as a cure for sarcomata and malignant growths. During the last 6 months the alleged remedy has been faithfully tried by many surgeons, but so far not a single well-authenticated case of recovery has been reported” [43,177]. Additionally, the FDA reclassified “Coley’s toxins” in 1963 as an investigational drug due to the absence of safety and efficacy data, despite more than 70 years of application and numerous published studies [43]. Despite facing initial skepticism, Coley’s work laid a cornerstone for future investigations into the intricate interplay between the immune system and malignant cells. Several years after his death in 1962, his toxins underwent reevaluation in a controlled trial, revealing their ability to induce anti-tumor effects [43,178]. Presently Coley’s principles, demonstrating that certain cancers respond positively to an augmented immune response has been validated and oncolytic virus therapies have been developed, employing genetically modified viruses to infect tumor cells, thus inducing a pro-inflammatory environment to bolster systemic anti-tumor immunity [179]. With vigorous research in the area of cancer immunotherapy, William B. Coley rightfully deserves and often regarded as the “Father of Immunotherapy” [43,180].

The mid-20th century ushered in a transformative period for scientific research, as investigators began to explore the intricate mechanisms underlying the immune system’s responses to tumors. During the 1950s and 1960s, pioneering work by scientists like Lewis Thomas and others brought significant advancements in the understanding of immune surveillance. This phenomenon describes the immune system’s role as a vigilant guardian, constantly monitoring and capable of recognizing and eliminating abnormal cells, including cancerous ones [98,181]. This groundbreaking concept laid the foundation for the modern understanding of tumor immunogenicity, emphasizing the innate capacity of the immune system to distinguish between self and non-self-antigens, including those presented by tumors [182].

In 1971, Professor Lloyd J. Old, a trailblazer in cancer immuno-oncology, observed that “there exists a distinct quality in cancer cells, setting them apart from normal cells, which the body’s immune system is capable of recognizing. He suggested that this unique attribute could be pivotal in understanding and harnessing the immune system’s ability to identify and combat cancer cells [183]. The subsequent decades witnessed a flurry of discoveries that further elucidated the complexities of tumor immunogenicity. Notably, the identification of tumor antigens in experimental animal models by researchers such as George Klein in the 1970s was an important scientific discovery [103,182]. George Klein played a key role in identifying tumor-associated antigens and tumor-specific antigens, contributing to our understanding that these antigens can be expressed by cancer cells at higher concentrations compared to normal cells [103]. However, research has since shown that the absolute specificity of these antigens might have limitations, and our understanding of their expression and immune response continues to evolve [184]. This pivotal insight paved the way for subsequent efforts to delineate tumor antigens in human cancers, laying the groundwork for the development of personalized immunotherapies tailored to individual patients’ tumor profiles. Advancements in molecular biology in the latter half of the 20th century catalyzed a paradigm shift in our understanding of tumor immunogenicity [185]. The discovery of oncogenes and tumor suppressor genes, unraveled the genetic underpinnings of cancer, unveiling a landscape marked by genetic alterations that drive tumorigenesis and shape the immunogenicity of tumors [186–188]. Importantly, mutations in oncogenes and tumor suppressor genes were found to give rise to neoantigens—novel antigens derived from mutated proteins expressed by cancer cells. These neoantigens, recognized as foreign by the immune system, emerged as promising targets for immunotherapeutic interventions aimed at eliciting potent anti-tumor immune responses [189–191].

The emergence of high-throughput genomic technologies in the 21st century has revolutionized our capacity to analyze the immune landscape of tumors with unparalleled accuracy [192–195]. Large-scale genomic projects, such as the Cancer Genome Atlas (TCGA), undertook the ambitious goal of cataloging the genomic alterations driving cancer across various tumor types [196,197]. Through comprehensive genomic analyses, TCGA and similar projects unveiled the heterogeneity of tumor antigens, including neoantigens, and provided invaluable insights into the molecular underpinnings of cancer immunogenicity [190,198]. These efforts laid the groundwork for the development of novel immunotherapeutic strategies aimed at exploiting the immunogenic potential of tumors for therapeutic benefit [199,200].

A significant milestone in the effort to leverage tumor immunogenicity for cancer therapy was the discovery of immune checkpoints—a class of inhibitory receptors that regulate immune responses and ensure immune homeostasis [8,147]. Through the advancement of therapies that inhibit specific checkpoints, such as ipilimumab (anti-CTLA-4), pembrolizumab and nivolumab (anti-PD-1), and atezolizumab and durvalumab (anti-PD-L1), scientists have harnessed the potential of the immune system, enabling it to generate robust anti-tumor immune reactions [147].

Advances in technologies such as next-generation sequencing have made it possible to identify neoantigens—antigens that arise from mutations specific to tumors [190,201,202]. This has opened the door to personalized cancer immunotherapy strategies, such as cancer vaccines and adoptive cell therapies, which are designed to target neoantigens specific to each patient’s unique tumor [190].

The notion that the immune system has the ability to recognize and destroy cancer cells was initially proposed by Paul Ehrlich in 1909 [99]. However, more precise concepts of tumor immunosurveillance developed from the pivotal observations made by Macfarlane Burnet and Lewis Thomas in the mid-20th century [40,110]. Building upon the earlier work of Paul Ehrlich and others, Burnet proposed the idea that the immune system plays a critical role in recognizing and eliminating cancerous cells, akin to its function in combating infectious pathogens [110,203]. Burnet expressed that “In large long-lived animals, like most of the warm-blooded vertebrates, inheritable genetic changes must be common in somatic cells and a proportion of these changes will represent a step toward malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character” [110]. He further hypothesized that neoantigens specific to tumor cells could trigger a potent immune response capable of eradicating emerging cancers [110,203]. This notion was further refined by Lewis Thomas, who introduced the term “immunosurveillance” to describe the immune system’s vigilant surveillance of the body for aberrant cells, including those with tumorigenic potential [111].

Although it initially faced skepticism, the concept of tumor immunosurveillance gained acceptance with the development of experimental models that showed the immune system’s capacity to identify and destroy tumors [114]. Studies in animal models, such as the observation of increased tumor incidence in immunocompromised mice and vice versa, provided compelling evidence for the existence of immunosurveillance mechanisms capable of suppressing tumor development [98,204,205]. Furthermore, clinical observations, such as the increased incidence of certain cancers in immunocompromised individuals, lent support to the notion of immune-mediated tumor suppression [206].

Tumor immunosurveillance involves a complex interaction between the immune system and cancer cells, driven by a wide range of cellular and molecular mechanisms [192]. Central to this process is the recognition of tumor-specific antigens by immune effector cells, including cytotoxic T lymphocytes (CTLs; CD8+ T cells) and NK cells, leading to the elimination of cancerous cells [114,204,207,208]. This recognition is facilitated by the presentation of tumor antigens by MHC molecules on the surface of antigen-presenting cells, such as DCs [209]. The innate immune system serves as the first line of defense against tumors, detecting and eliminating transformed cells through a variety of mechanisms [210]. NK cells, endowed with the ability to recognize and kill aberrant cells lacking self MHC class I molecules or abnormal/altered MHC class I expression, play a pivotal role in tumor immunosurveillance [211,212]. Additionally, macrophages and DCs contribute to the elimination of cancer cells through phagocytosis and antigen presentation, respectively, initiating adaptive immune responses against tumors [213,214]. The adaptive immune system provides a more specialized and potent response to cancer cells, especially mediated by antigen-specific T lymphocytes [3,215]. CTLs recognize and eliminate cancerous cells expressing tumor-specific antigens in the context of MHC class I molecules, while helper T cells orchestrate the immune response by secreting cytokines and activating other immune cells [216,217]. While B lymphocytes have the capacity to generate antibodies directed at tumor antigens, the significance of humoral immune responses in combating cancer is controversial and a subject of debate [218].

Beyond cellular immunity, soluble factors like cytokines and chemokines are vital to tumor immunosurveillance [219]. Interferons, ILs, and tumor necrosis factor-alpha directly combat tumors by triggering apoptosis, suppressing cell proliferation, and boosting immune cell activity. Chemokines, on the other hand, manage the movement of immune cells to the tumor site, aiding in their infiltration and the subsequent elimination of the tumor [220].

Immuno-evasion mechanisms employed by cancer cells represent a complex array of strategies meticulously orchestrated to evade the host immune system’s surveillance and thwart immune-mediated destruction [115]. These mechanisms reflect the remarkable adaptability of cancer cells in evading recognition and eradication by the immune system, thereby promoting tumor growth, progression, and metastasis [115,221].

The success of checkpoint inhibitors, such as ipilimumab (yervoy) (anti-CTLA-4), pembrolizumab/cemiplimab (Libtayo)/nivolumab (anti-PD-1), and atezolizumab/avelumab (bavencio)/durvalumab (imfinzi) (anti-PD-L1), has revolutionized cancer treatment. These therapies work by blocking inhibitory pathways that prevent T-cells from attacking cancer cells [147,282]. In future, combining these inhibitors with other treatments, including additional immunotherapies, targeted therapies, and conventional treatments like chemotherapy and radiation, can have promising results. Combining therapies can lead to synergistic effects, enhancing the overall anti-tumor response and potentially overcoming resistance mechanisms.

CAR-T cell therapy represents a significant leap in personalized cancer treatment. By genetically modifying a patient’s T-cells to express receptors specific to cancer antigens, CAR-T cell therapy has shown substantial success in hematologic cancers like leukemia and lymphoma [283,284]. Future research aims to extend this therapy to solid tumors, improve its safety and efficacy, and reduce side effects such as cytokine release syndrome. Advances in gene editing technologies, including CRISPR/Cas9, are expected to further refine and enhance CAR therapies. CAR-M and CAR-NK cells are promising candidates [285–288].

Adoptive T-cell therapy (ACT) involves expanding and reinfusing a patient’s own T-cells that have been activated to fight cancer. This approach has shown promise in treating various cancers and is continually being refined [289,290]. Efforts in positive directions led to, lifileucel, receiving US FDA approval on February 15, 2024, as the first cellular therapy for solid cancer [82]. Future developments in ACT include enhancing the specificity and persistence of T-cells, optimizing the expansion process, and combining ACT with other immunotherapies to boost effectiveness.

Gene editing technologies, particularly CRISPR/Cas9, have opened new avenues for cancer immunotherapy [291]. These tools enable precise modifications to immune cells, enhancing their ability to target and destroy cancer cells. Additionally, cellular reprogramming techniques, such as converting fibroblasts into DCs, are being explored to create more effective cancer vaccines and therapies [292]. These innovations have the potential to generate personalized treatments, according to individual patients’ tumor profiles.

Immune system’s ability to remember cancer antigens offers the potential for long-term remission. Research is focused on understanding how to stimulate and sustain immune memory responses to prevent cancer recurrence [293,294]. Vaccines and therapies that enhance immune memory are being developed to provide lasting protection against cancer [295].

The TME, including the surrounding stroma, immune cells, and vasculature, plays a crucial role in cancer progression and response to therapy [240]. Modulating the TME to enhance immunotherapy effectiveness is a key area of research. Additionally, the microbiome—the community of microorganisms in the body—has been found to influence cancer treatment outcomes [296]. Table 2 depicts the various immunotherapy clinical trials in phase 1 [297–310]. Manipulating the microbiome through approaches like fecal microbiota transplantation could improve responses to immunotherapy [311].

Identifying biomarkers that predict responses to immunotherapy is essential for personalized cancer treatment [312]. Researchers are actively investigating additional biomarkers to enhance patient selection and optimize therapeutic outcomes [313]. Tumors with high mutational burden or specific genetic features, such as microsatellite instability, are known to respond better to certain immunotherapies [314,315]. Personalized approaches based on these biomarkers can enhance treatment efficacy and reduce adverse effects.

Despite the success of immunotherapy, some patients develop resistance or relapse after treatment [316,317]. Understanding the mechanisms of resistance is important for developing strategies to overcome it [318]. This includes targeting multiple immune checkpoints, enhancing antigen presentation, and preventing the development of escape mutations [318–320]. New therapeutic combinations and novel agents are being explored to address resistance and improve long-term outcomes.