Trained immunity: A new player in cancer immunotherapy

Abstract

In the past, immune memory was considered an exclusive feature of the adaptive immune system. However, accumulating evidence suggests that the innate immune system, the most primitive and fundamental component of immunity, can mount more robust responses to non-specific stimuli following prior exposure to different types of initial stimuli, a phenomenon known as trained immunity. Trained immunity has been extensively studied in diverse disease contexts, including infectious diseases, autoimmune disorders, and chronic inflammatory conditions. Notably, significant advancements have been made in recent years in understanding the roles and therapeutic potential of trained immunity in oncology. This review aims to explore the multifaceted roles of trained immunity across different cancer types, providing a comprehensive summary of the pertinent stimuli and associated molecular mechanisms. Additionally, we evaluate the clinical applications of various trained immunity stimuli in cancer therapy and offer perspectives on future directions for integrating trained immunity into cancer treatment strategies.

Keywords: cancer immunotherapy; immunology; inflammation; innate immune cells; trained immunity.

Figure 1.. Chronology of significant milestones in research on trained immunity and cancer treatment.

This timeline highlights major developments in trained immunity from 1961 to 2024. The concept originated with the discovery of Systemic Acquired Resistance (SAR) in plants (118) and was formally introduced as ‘trained immunity’ in 2011 (Netea et al., 2011). In 2014, omics studies identified key epigenetic modifications associated with trained immunity (Saeed et al., 2014). By 2018, research demonstrated that trained immunity could mobilize hematopoietic progenitors to establish long-term innate immune memory (Mitroulis et al., 2018). In 2020, trained neutrophils were shown to exhibit antitumor effects (Kalafati et al., 2020), and trained immunity was proposed as a strategy for cancer treatment (Kalafati et al., 2020; Priem et al., 2020). Subsequently, trained macrophages were found to control pancreatic cancer, melanoma, and lung metastases (Geller et al., 2022; Wang et al., 2023; Ding et al., 2023). Most recently, in 2024, clinical trials have explored the use of β-glucan and Bacillus Calmette-Guerin (BCG) vaccines to induce trained immunity (ClinicalTrials.gov). This figure illustrates the evolution of trained immunity research and its potential applications in cancer therapy. This figure was created using FigDraw.

Figure 2.. Epigenetic and metabolic reprogramming associated with trained immunity in cancer treatment.

(a) Intracellular pathway changes associated with trained immunity. Compared to resting cells (gray), immune cells exposed to an initial stimulus exhibit augmented epigenetic modifications, elevated expression levels of mTOR and HIF1α, and increased mitochondrial fission (yellow). In addition, surface markers such as CD80, CD86, and MHC II are upregulated, indicating a pre-activated state. Notably, at this stage, the cells’ ability to secrete cytokines and phagocytose bacteria remains unaltered. Upon exposure to a secondary stimulus, these cells (red) transition into a fully activated state, characterized by increased production of reactive oxygen species (ROS) and cytokines, thereby enhancing their tumoricidal efficacy. (b) The differential effects of tumor-associated factors on hematopoiesis. In the absence of trained immunity-inducing stimuli, tumor-derived factors promote the differentiation of immunosuppressive myeloid cells including neutrophils and macrophages from bone marrow progenitors. These cells infiltrate the tumor microenvironment, leading to immune cell suppression, exhaustion, or dormancy. In contrast, exposure to trained immunity-inducing agents induces myelopoiesis, facilitating the mobilization of a greater number of trained monocytes and/or neutrophils into the peripheral circulation. Consequently, more activated immune cells accumulate within and around the tumor, collectively suppressing tumor progression and metastasis. Abbreviations: CMP, common myeloid progenitors; GMP, granulocyte–macrophage progenitors; HIF1α, hypoxia-inducible factor 1 alpha; HSC, hematopoietic stem cells; mTOR, mammalian target of rapamycin; MPP, multipotent progenitors. This figure was created using FigDraw.

Figure 3.. Induction of trained immunity in different tumors.

The tumor-promoting or tumor-suppressing roles of various trained immunity inducers, such as BCG and β-glucan, across different cancer types are illustrated. An upward red arrow indicates an enhanced effect or tumor-promoting activity, while a downward blue arrow denotes inhibition of tumor progression. Abbreviations: BCNS, brain and central nervous system tumors; CDN, cyclic di-nucleotide; CTB, cholera toxin B; IRE, irreversible electroporation; MIF, macrophage migration inhibitory factor; MTP10-HDL, a new nanobiologic candidate; PC, phosphatidylcholine; TI, trained immunity. This figure was created using FigDraw.