Aplastic anemia (AA) is an acquired form of autoimmune hematopoietic failure (AHF). Traditionally, AA has been considered a benign hematological disease. AA pathogenesis results from the destruction of hematopoietic progenitor cells (HPCs) by deranged autoimmune responses that occur mainly in the bone marrow (BM) environment (BME). After an initial insult by pathogenic environmental challenges, such as genotoxic exposure or microbial infection, the activated immune responses perpetuate and result in immune-mediated impairment of blood cell production and subsequent clinical presentations of BM hypoplasia/aplasia and peripheral cytopenia in one or more cell lineages (1, 2). Currently, the diagnosis of AA is largely based on markedly decreased BM cellularity and hematopoietic volume with fatty replacement and the absence of overt dysplastic hematopoiesis in HPCs (3, 4). AA is a highly heterogeneous disease entity that converges on a pathophysiological process of persistently deranged autoimmune responses and heavily exhausted HPCs. Patients with AA exhibit varying clinical presentations regarding disease phenotype, disease severity, disease course, treatment response to immune suppressants, and the likelihood of transformation to myeloid neoplasms (MNs). This high heterogeneity is driven by the diversity of the constitutional genetic background, the competence of innate immune cells, the appropriateness of adaptive immune responses to environmental challenges, basic functions of other organ systems, events that guide immune responses, and perhaps most importantly, conditions that sustain deranged autoimmune reactions (1–4).

Myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML) are unequivocal MNs. MNs result from the acquisition and accumulation of somatic mutations in HPCs. Genetic damage is generated from the exposure of HPCs to various oncogenic agents, and the emergence of leukemic clones arises from the selective advantage of transformed HPCs in the context of chronic inflammatory BME. Oncogenic mutations in transformed HPCs lead to altered proliferation, self-renewal, and antiapoptotic capacity. The dysregulated growth of leukemic cells results in the overgrowth of their normal counterparts and the suppression of normal blood cell production, clonal hematopoiesis, and corresponding hematological presentations (5–8). The presence of dysplastic features indicates a diagnosis of MNs, and an increased percentage of myeloblasts is the most significant biomarker representing leukemic hematopoiesis and entry into advanced stages (9, 10). Immunological, cytogenetic, and biological molecular analyses can provide valuable information for diagnosis, classification, and risk stratification. MDS, MPN, and AML are also highly heterogeneous with somatic mutations involving hundreds of genes in association with their pathogenesis. Each somatic mutation plays a distinctive role in malignant transformation or affects clinical complications, hematological presentations, cellular components, immunological signatures, disease progression, and treatment response (5–8).

Accumulating evidence supports that there is an intrinsic relationship between AHF and MNs regarding their clonal hematopoiesis, immunological profile, and disease phenotypic transformations.

By definition, AA is distinct from MDS, MPN, and AML with differences in fundamental pathogenesis, biological behaviors, laboratory features, treatment strategies, and prognostic significance. However, disease phenotypes can transform between AHF and MNs. The natural transformation of AA to MNs has been widely investigated (11–14) and is generally ascribed to the acquisition and accumulation of oncogenic mutations due to selective pressure and immune exhaustion in the setting of a chronic inflammatory milieu (15–18). It is well known that antithymocyte globulin (ATG) plus cyclosporine-based immunosuppressive therapy (IST) promotes leukemic transformation. Approximately 10%–15% of patients with severe aplastic anemia (SAA) experience leukemic transformation following IST, and in some patients, this transformation emerges during or shortly after IST (19–23). Such a short interval that spans the transformation process indicates that leukemic clones preexist in the SAA stage (24–27) and rapidly expand due to depletion of cytotoxic T lymphocytes (CTLs) or the induction of immune tolerance (28–32) rather than due to the acquisition of novel molecular events. In patients with genetic aberrations typically observed in MNs, there is a greater frequency of transformation to MNs. Moreover, 20%–30% of SAA patients fail to respond to IST, and these patients have a significantly greater frequency of MN-related genetic aberrations compared to patients who achieve a good treatment response. Even in patients who achieve a hematological response, the presence of MN-related genetic aberrations is associated with a reduced sensitivity to IST, a low rate of deep remission, a high frequency of disease relapse, and a significantly increased risk of leukemic transformation (19–23).

Leukemic transformation in SAA patients can also occur after successful treatment of underlying infections and is frequently separated by a short duration of hematological remission. A rapid increase in leukemic blasts is the representative presentation of leukemic hematopoiesis (33–35). Moreover, patients with definitively diagnosed MNs can develop an aplastic crisis during infectious episodes. During aplastic crisis, the cytological and immunological features resemble those of SAA with a regression of leukemic blasts (35, 36). It remains unclear why patients with a similar genetic landscape or even an identical genetic background exhibit variable disease phenotypes. Furthermore, the significance of disease phenotypic transformations has not been fully elucidated through basic research and clinical practice. It is possible that environmental factors, most likely changes in inflammation strength or depletion of effector immune cells, affect the disease phenotype and contribute to phenotypic transformations (as schematized in Figure 1 ).

With the wide application of next-generation sequencing (NGS) in the diagnosis, mutational analysis, and risk stratification of hematological diseases (37, 38), it has been shown that more than one-third of patients definitively diagnosed with AA carry genetic aberrations that are well-known driver mutations in MNs (19–27). Although the number and clone size of mutant genes in AA are much smaller than those in MDS and AML, the number and clone size of these mutant genes can increase in patients who respond to IST (20–22). Currently, AA is also known to be a clonal hematological disease. Clonal HPCs gain a selective proliferative and survival advantage over their normal counterparts in a chronic inflammatory setting and become the dominant hematopoietic components (24–27). Moreover, some patients with MDS or AML can present heavily reduced BM cellularity at initial diagnosis or during disease progression, and patients with low-risk MDS have an immunological landscape similar to that of SAA (39–43).

AA and hypoplastic MDS (hMDS) are typical forms of immune-mediated AHF, and they share similar cytological and immunological landscapes (39, 40). In AHF, autoimmune CTLs (43–45) and natural killer (NK)/NKT cells (46–48) become activated and expanded. Trained CTLs [effector memory CTLs (emCTLs)] and NK/NKT cells (effector memory NK/NKT cells) exhibit elevated killing activities (43–48), increased secretory capacities (49–51), and enhanced sensitivities to antigen stimulation (52, 53). The oligoclonal feature of expanded emCTL infiltrating the BM suggests the presence of chronic stimulation that is driven by an antigen from the BME (43, 50). The excessive production of hematopoietic inhibitory mediators (54–57) due to T helper type 1 (Th1) immune responses (58–60) plays a central role in AHF pathogenesis. Additionally, upregulated expression of proapoptotic molecules (61–63) and decreased telomerase activity (64, 65) accelerate the death of HPCs. Upregulated expression of Toll-like receptors (TLRs) and costimulatory molecules in response to chronic inflammation enhances sensitivity to antigen stimulation, propagates inflammatory responses, induces the production of reactive oxygen species, augments apoptotic signals, amplifies pyroptoptic cell death, and favors a selective survival advantage, which forms a positive feedback loop to cause ineffective hematopoiesis and sustain clonal proliferation (66–69). Moreover, the number and function of regulatory T cells (Tregs) and regulatory B cells (Bregs) are dramatically decreased (70–73), as is the downregulation of anti-inflammatory mediators (74–76). Defects in HPCs and dysregulation of immune responses are also present in complete remission following IST (77, 78). Autoimmunity targeting HPCs by autoantigen-specific lymphocytes (50, 59) attracts a variety of immune cells (79–81). Immune cell infiltration and activation create an immune-active BME (79–83), which forms an inflammatory background and may determine a BM-predominant autoimmune impairment (39–42). The BM-predominant autoimmunity is amplified by an additional antigenic stimulation (84–87). Th1 immune responses suppress the production of erythrocytes, granulocytes, platelets, and B lymphocytes (49, 55–57, 87), which results in clinical and laboratory features of AA and hMDS (3, 4, 9, 10).

The development of an immune-active BME can be achieved in several ways. 1) Pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), or antigen-specific CTLs target pathogenic antigens of microbes that can survive and smolder in BM cells (84–87). 2) Cellular components that cross-react with microbial epitopes are targeted by autoimmune lymphocytes trained in active infectious diseases (88), particularly inflammatory conditions involving the gastrointestinal tract (89, 90), which can continuously supply intestine-derived antigens from pathogenic or commensal microbes in the context of increased epithelial permeability (90–92). 3) Somatic mutations in epigenetic modulators or transcription factors lead to the excessive production of inflammatory cytokines (93, 94). 4) PRRs sense damage-associated molecular patterns (DAMPs) (95–98), or autoimmune CTLs target neoplastic antigens of genetic or epigenetic products (40, 59, 99–101) in transformed HPCs. If autoimmune responses target DAMPs or neoplastic antigens on leukemic HPCs, the role of autoimmune responses in AHF may be antileukemic (95, 97, 102).

In 2009, Nissen (231) proposed that autoimmune responses occurring in acquired AA may function as an antileukemic mechanism against malignant proliferation. In the SAA stage, the decreased number and function of Tregs and Bregs, the decreased production of inhibitory cytokines, the reduced expression of coinhibitory molecules, the increased Th1 responses, the increased number and function of CTLs and NK/NKT cells, the increased antigen-presenting activities, and the excessive expression of proapoptotic and costimulatory molecules on HPCs may represent an adaptive process in response to ongoing antigen stimulation. Along with disease progression, the immunological signature in the BME is transformed from a Th1-predominant response to an immune exhaustion state in which the function of infiltrated autoimmune lymphocytes is inhibited and immune surveillance is gradually dampened in adaptation to the chronic inflammatory milieu. The immune exhaustion state favors leukemic cell survival and facilitates the penetration of symptomatic MNs (15–18). The extrapolation was mainly drawn from tumor regression and concomitant autoimmune phenomena in diseased organs during the treatment of non-hematological malignancies with immunological therapy. The author also described examples of hematological neoplasms in which leukemic cell regression was observed along with the appearance of prolonged aplastic cytopenia and autoimmune reactions (AA-like syndrome) after intensive chemotherapy or other treatment modalities. The author coined the phrase “pancytopenia of unknown significance” to describe this clinical phenomenon. Severe BM hypoplasia, systemic inflammatory symptoms, increased autoreactive CTLs, and decreased Tregs were observed in this AA-like syndrome. These cytological and immunological features indicate that antileukemic immunity has been reinvigorated.

Indeed, AHF can occur in response to neoplastic antigens or DAMPs (95, 96, 102, 232). The acquisition of autoantibodies against the neoplastic antigen carbonic anhydrase I induces AA-like syndrome and leukemic cell regression (102). Constitutive activation of the RAS-MAPK pathway can induce HPC senescence (96), and the absence of PRRs that sense neoplastic molecules results in accelerated leukemia cell proliferation (97). Similar to solid tumors (233–235), immune responses to neoplastic antigens (99–102) and stress in response to HPC damage (95–97) establish a chronic inflamed BME (93, 94, 236, 237). The inflamed BME enhances sensitivity to exogenous antigen stimulation (52, 66, 67) and accelerates apoptotic death in leukemic (95, 96, 238, 239) and normal (95, 96, 142, 143) HPCs, which are the common clinical and laboratory features of AA and low-risk MDS (39, 40, 49, 240) (as schematized in Figure 2 ).

Antileukemic immunity-induced Th1 responses preferentially repress leukemic cells and their normal counterparts, which can lead to pronounced neutropenia (42, 102, 232). Autoimmune neutropenia can persist for many years prior to the emergence of symptomatic MNs. In this stage, the BM is hypocellular, and cytological and immunological features exhibit immune-mediated hematopoietic impairments in the absence of morphologically identifiable leukemic blasts (241, 242). A significant proportion of MDS patients with overt dysplasia present with hypocellular BM and peripheral pancytopenia at initial diagnosis or during disease progression and these patients frequently have longer survival (21, 23, 42, 240). Prolonged neutropenia after intensive chemotherapy has been associated with deep remission, longer remission duration, reduced frequency of relapse, and restoration of Th1 immune responses (243, 244). Substantial evidence supports an antileukemic role of autoimmune responses in AHF (42, 95, 102, 232), at least in a large number of AHF patients who have MN-related genetic aberrations (19–26). However, factors underlying the exaggerated autoimmune responses that influence antileukemic activities and disease phenotypes were not discussed in Nissen’s manuscript (231).

The transformation between AHF and clinically overt MNs (MDS with excessive blasts or AML in which an increased percentage of myeloblasts is the most representative parameter in determining leukemic hematopoiesis) can reciprocally occur. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammatory conditions (33–36). Extramedullary infectious diseases have a conspicuous impact on phenotypic presentations. During active inflammatory episodes, normal and leukemic hematopoieses are simultaneously suppressed with regression of leukemic blasts on cytological examination and Th1-predominant responses on immunological analysis. Aplastic cytopenia, the disappearance of leukemic blasts, Th1-predominant responses, and a small number of nucleated blood cells for identification of dysplasia result in cytological and immunological features that meet the criteria for the diagnosis of AA (33–36). Following successful control of the inflammatory episodes and a short duration of hematological remission, quickly expanded leukemic clones lead to the appearance of substantial leukemic blasts and symptomatic MNs (33–35). Patients with clinically overt MNs can develop an aplastic crisis during active inflammatory episodes in which systemic inflammatory stress is dramatically aggravated (35, 36). Within this period, the BM becomes aplastic/hypoplastic, and leukemic blasts disappear with the infiltration of autoimmune lymphocytes. These phenomena indicate that autoimmune responses in AHF are an inflammatory stress-powered antileukemic mechanism. Immune surveillance against leukemic blasts contributes to BM-specific autoimmune impairments, while inflammatory stressors strengthen autoimmune responses (as schematized in Figure 3 ).

This process simulates spontaneous remission in AML patients after an infectious episode and aplastic crisis (245–252). The mechanism is presumed to be due to reversion of the immune exhaustion state and restoration of antileukemic immunity through activation of immune cells and their secretion of proinflammatory cytokines in response to invading pathogens (250–253). Another frequent situation that induces spontaneous remission is that patients with hypoplastic AML (hAML) are treated with hematopoietic growth factors. To date, spontaneous remission has been reported in more than 200 AML patients. The remission duration usually lasts for 2–6 months, which indicates that leukemic clones cannot be eradicated even under inflammatory stress-powered antileukemic immunity (245, 254). This may be due to the low expression of neoplastic antigens on dormant leukemic cells (255–258). However, repeated spontaneous remissions occur in a paucity of patients (245, 247), which suggests that patients do not completely lose the hematopoietic regulatory mechanisms and the inflammatory stress-powered antileukemic immunity. Another interesting phenomenon also suggests the existence of inflammatory stress-powered antileukemic activities (243, 244). Prolonged neutropenia due to hematopoietic suppression in AML patients after intensive chemotherapy is usually complicated by durable or repeated infectious episodes, which frequently result in death. If patients survive prolonged neutropenia, they may achieve deep remission, longer remission duration, and a reduced frequency of relapse. Recombinant type I inflammatory cytokines (259–262), interferon inducers (263–265), and BCG inoculation (266–268) have been used to treat hematological and non-hematological neoplasms and have shown efficacy in the control of tumor growth or even the clearance of malignant clones. Other vaccine inoculations that can stimulate Th1 responses have also been shown to have antitumor effects (269–271). These non-specific immunological therapies and their treatment effects indicate that inflammatory stressors, rather than antigen-specific responses to invading pathogens, augment antitumor activities (139).

Immune exhaustion in adaptation to persistent inflammatory stimulation is a common mechanism underlying the escape of leukemic clones from immune surveillance (17, 18). Hyporesponsiveness is characterized by a high infiltration of negative immune cells, excessive secretion of anti-inflammatory cytokines by immune regulatory cells, and high expression of immune checkpoint molecules on tumor cells in the tumor microenvironment, which work to limit the magnitude of inflammatory responses, avoid excessive tissue damage, and maintain a dynamic immune balance in the context of chronic inflammatory stressors (272, 273). In an immune exhaustion state, dampened antileukemic immunity favors leukemic cell escape from immunological attack and facilitates the penetration of symptomatic MNs. ICIs block coinhibitory molecules and reinvigorate antitumor immunity. ICIs have been successfully used to treat MNs (273–275), and a high-grade inflammatory profile in the BME is a predictor of a good therapeutic response to ICI treatment (276, 277) and suggests that antileukemic immunity is closely related to an inflamed BME. The relationship between an inflamed microenvironment and ICI treatment response has been more thoroughly studied in solid tumors (234, 278–280).

It is widely accepted that dysbiotic gut microbiota plays an important role in promoting tumor cell escape from immune attack in solid tumors (281–283), and the response to ICI treatment is strongly influenced by the abundance and diversity of the gut microbiome (284, 285). This also indicates that antitumor immunity necessitates the engagement of additional antigenic stimulation for immune surveillance against neoplastic antigens. A reduced gut microbial abundance and diversity due to antibiotic treatment can dramatically dampen ICI treatment responses (286). Modulation of the gut microbiota can reverse the dampened responses (287–290). Some pathogenic (291–295) and commensal (296, 297) microbes can stimulate Th1 immune responses and thereby power antitumor immunity (298–300) and enhance ICI treatment responses (301–303). One of the major adverse effects of ICI treatment is hematological toxicity (304–306), especially when treating hematological malignancies and when combined with other antileukemic agents (306). This reinforces the role of Th1 responses in AHF pathogenesis and inflammatory stress-related antileukemic immunity.

Blood cells are immune cells, and their production is regulated largely in response to microbial invasion. Therefore, hematopoietic cells are more sensitive to inflammatory mediators. When confronting an acute and limited infection, HPCs sense microbial antigens and inflammatory cytokines. With the pathogenic stimulation, host hematopoiesis proliferates and polarizes the differentiation toward the production of effector immune cells to fight invading microbes and replenish the consumed innate immune cells (307–310). However, chronic inflammatory stress in response to persistent intracellular infections can induce Th1-predominant immune responses and exhaust host hematopoietic functions. These responses predominantly exhaust granulopoiesis, erythropoiesis, megakaryocytopoiesis, and B lymphopoiesis (311–316) and result in the morphological and immunological signatures shown in AHF (3, 4, 10, 240). The upregulated expression of HLA-DR, TLRs, and the Nlrp3 inflammasome due to the primary immune-active BME increases sensitivity to antigen stimulation (50, 52, 66, 67) and apoptotic death of HPCs (50, 62, 63). In combination with extramedullary inflammatory stressors, the immune-active BME leads to BM-specific and inflammatory stress-powered autoimmune responses. In the absence of an inflamed BME, some infectious diseases, although able to induce Th1 immune responses, may not seriously injure hematopoietic function. Evidence for this is that patients with systemic rheumatic diseases are seldom complicated by AHF. Along with the persistence and exacerbation of inflammatory stressors, the host immune system can be impaired, which changes the immunological landscape from the proinflammatory phenotype of AHF to the immune exhaustion phenotype of advanced MN (317–320). Exhausted immune responses and DNA damage occurring under chronic inflammatory conditions are considered major contributors to the immune escape of leukemic cells (15, 16, 321, 322). The role of immune exhaustion in advanced MN may cause an increased threshold for effective antileukemic immunity (323). Enforcing an additional antigen stimulation or administrating ICIs can reverse the immune exhaustion state and thereby overcome the raised threshold and restore missed antileukemic immunity (35, 95, 250, 253, 323). Combination of immune-stimulating agents and ICI treatments may further potentiate antitumor activities (as schematized in Figure 4 ).

From this point of view, AHF and MNs have complex intrinsic relationships, and some patients with definitively diagnosed AA may be hMDS (39, 40, 324, 325) or hAML (102, 232). The absence of overt leukemic hematopoiesis in AHF likely results from the small number of nucleated cells available for identification of aplasia and leukemic blasts due to severe BM hypoplasia and a preferential attack on transformed HPCs by autoimmune CTLs and their secretion of hematopoietic inhibitory mediators (238, 239, 259–262). Indeed, neutropenia is a common preleukemic presentation in MNs, and in a significant proportion of MDS patients, neutropenia can be a solitary hematological abnormality that persists for many years (241, 242). Furthermore, a poor response to hematopoietic growth factors predicts a high frequency of disease progression (242). A decreased white blood cell count and concealed leukemic clones make it difficult to distinguish this AA-like syndrome from genuine AA (39, 40, 324, 325), which leads to a diagnosis of AA in most circumstances (3, 4), especially before the wide application of NGS in the diagnosis and stratification of hematological diseases.

AHF is an organ-specific AID. Autoimmune responses occur predominantly in the BM and result in the exhaustion of HPCs and impairment of mature blood cell production (1, 2, 39, 240). AA and hMDS are clonal hematological diseases (5, 25, 27, 240). Genetic aberrations in clonal hematopoiesis affect cell proliferation, self-renewal, and apoptosis (5–8). While hMDS is an unequivocal MN, AA has a high frequency of transformation to MNs. The natural evolution from AA to MNs is usually a long-term process (11–14) and is frequently attributed to genetic damage or immune exhaustion due to an inflamed BME (15–18). However, leukemic transformation can occur during or shortly after IST (19–23). Effective treatment of underlying infections can also induce leukemic transformation (33–35). Prior to the emergence of symptomatic MNs, patients usually experience a short duration of hematological remission. Leukemic transformation shortly after IST or treatment of underlying infections may better reflect the intrinsic relationship between AHF and MNs with regard to the influence of the host immunological state on the disease phenotype. This is because IST and treatment of underlying infections can rapidly change the host immune state without inducing novel genetic damage. An aplastic crisis with leukemic cell regression in definitively diagnosed MNs during inflammatory episodes provides a more persuasive argument for the influence of the host immune state on the disease phenotype (35, 36).

Although patients with MNs may benefit from inflammatory stress-powered antileukemic immunity, an excessive inflammatory cascade and severe cytopenia can be harmful or even fatal. Like in other AIDs (156–161), AHF pathogenesis necessitates an active chronic inflammatory condition in addition to the inflamed BME to sustain BM-predominant autoimmune impairment (90, 95, 161, 313, 315). When AHF patients present with active inflammatory symptoms and their cytopenia is dramatically exacerbated, identifying and disposing of inflammatory niduses are urgent tasks that are needed to save patients’ lives. In this situation, particular attention should be given to inflammatory diseases in the gastrointestinal tract and disseminated tuberculosis. Tuberculosis reactivation may be the result of an immune exhausted state and/or the administration of immune suppressants. Disseminated tuberculosis can worsen hematopoietic function and become a major health problem in AHF patients.

Autoimmune responses in AHF may represent an inflammatory stress-powered antileukemic mechanism, at least in a significant proportion of patients whose pathogenesis is associated with MN-related genetic aberrations. With age, the incidence of clonal hematopoiesis increases, which is known as mutation-specific adaptation to environmental stressors and is consistent with a high incidence of AHF and inflammatory disorders in old age. However, age-related clonal hematopoiesis also increases the risk of malignant evolution (383–385). A dynamic balance between antileukemic activities and negative immune regulators may play a more important role in the suppression of transformed HPCs and the maintenance of effective hematopoiesis in old age. In this process, immune surveillance against neoplastic antigens or DAMPs initiates a primary inflammatory background in the BME and may contribute to the BM-specific autoimmune impairment. Extramedullary inflammatory stressors generated from exogenous antigen stimulation, especially from the gastrointestinal tract and chronic intracellular infections, play a critical role in the sustenance of autoimmune responses and the apoptosis of HPCs and promote the development of AA-like syndrome.

Although AA and MNs are generally considered distinctive disease entities, the phenotype of aplastic cytopenia can transform into MNs and vice versa. The switch that shapes the disease phenotype is a change in inflammation strength. During active infectious episodes, leukemic blasts can regress due to the reversion of the immune exhaustion state and the restoration of antileukemic activities. At this time, patients manifest aplastic cytopenia. After successful treatment of underlying infections, leukemic clones rapidly expand, and patients manifest symptomatic MNs, which commonly follow a short duration of hematological remission. Miscellaneous microbes or even endotoxins can induce antitumor immunity. This indicates that not antigen-specific stimulation but rather inflammatory stressors in response to microbial invasion are responsible for sustaining antitumor activities. Although they occur through different mechanisms, the effect of ATG-based IST is similar to that of treating underlying infections. Spontaneous remission in AML patients and non-specific immunological therapies in treating hematological malignancies may share an inflammatory stress-powered antileukemic mechanism.

An in-depth investigation of inflammatory stress-powered antileukemic immunity is highly important for theoretical research and clinical practice. Understanding the mechanisms of immune surveillance against malignant proliferation and the rational administration of immune-activating agents and ICIs in the treatment of hematological malignancies will be helpful, especially when aplastic cytopenia appears to be the major adverse effect. Some pathogenic microbes can stimulate Th1 responses. Inoculation of vaccines from these microbes has direct antileukemic effects and enhances ICI treatment efficacy. The inflammatory stress-powered antileukemic mechanism raises many questions.

Collectively, inflammatory stress-powered antileukemic immunity warrants extensive investigation. This may explore a new way of MN treatment. With in-depth investigations, many questions will emerge, and better strategies for improving treatment responses and managing adverse complications will be found.

X-CZ: Conceptualization, Writing – original draft. BJ: Data curation, Writing – original draft. N-NX: Data curation, Writing – original draft. X-YS: Data curation, Writing – original draft. F-JM: Supervision, Writing – review & editing.