Progress in the research of immunotherapy‑related hyperprogression (Review)

  • Authors:
    • Ruizhe Qi
    • Lihui Yang
    • Xinchao Zhao
    • Liying Huo
    • Yaling Wang
    • Peifang Zhang
    • Xiaomei Chen
  • View Affiliations

  • Published online on: November 17, 2023
  • Article Number: 3
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Immunotherapy has become an effective method for the treatment of a variety of malignant tumors. However, with the development of immunotherapy, the phenomenon of hyperprogression in patients with cancer has gradually attracted attention. Hyperprogression refers to a condition in which the progression of a disease during treatment of a patient with cancer is suddenly accelerated. To date, no reliable marker has been found to predict accelerated tumor growth during immune checkpoint inhibitor (ICI) treatment. The aim the present study was to summarize the definition of hyperprogression and the difference between hyperprogression and pseudocytosis, and investigate the potential mechanisms of hyperprogression including clinical characteristics, potential molecular markers and the immune microenvironment. The effect of macrophage‑related different types and factors on tumors in the immune microenvironment was analyzed, and the findings may be used to determine the future directions of research in hyperprogression.

1. Introduction

Malignant tumors are one of the main diseases that seriously threaten human health, with the incidence and mortality rates increasing annually in China. During the past two decades, immunotherapy has become the fourth main method of treating cancer, following surgery, radiotherapy and chemotherapy. Several types of immunotherapy have been developed, such as ICIs, immunomodulatory drugs, monoclonal antibodies, cancer vaccines, and chimeric antigen receptor T cells (CAR-T). Among them, immunotherapy, in the form of ICIs, has been shown to have an unprecedented impact on the prognosis of patients with multiple tumor types. ICIs reactivate the immune response of T cells by inhibiting the activity of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) receptors to exert antitumor effects (1). ICIs have a strong specificity and lasting effect.

However, not all patients have access to ICIs, and a small number of patients have accelerated disease progression following ICI treatment, namely, hyperprogressive disease (HPD) (2). HPD is not limited to immunotherapy; it also occurs in targeted treatment, as well as traditional chemotherapy. The incidence of HPD increases and the overall survival of patients is shortened following immunotherapy, which suggests that the occurrence of HPD seriously affects the prognosis of a patient (3-5). Recently, there have been several hypotheses regarding the development of HPD in immunotherapy, take for example, immune checkpoint blockade which has the potential to functionally stimulate regulatory T cells (Tregs) and locally form an immunosuppressive tumor microenvironment (TME); blockade of immune checkpoints induces polarisation of immunosuppressive cells such as M2 macrophages and dendritic cells that produce high amounts of immunosuppressive cytokines. HPD is both a challenge and an opportunity for immunotherapy. As the current understanding of HPD is very limited, an in-depth exploration of HPD is urgently needed. In the present study, the definition and evaluation criteria of HPD, related influencing factors (clinical and molecular), differential diagnosis and the establishment of clinical plans, were reviewed to provide a reference for further HPD-related research, reasonable prediction and stratification prior to clinical treatment, as well as guidance for individualized immunotherapy.

2. Discovery process and evaluation criteria of HPD

In 2016, Chubachi et al (6) were the first to report that patients with non-small cell lung cancer (NSCLC) receiving navurlizumab exhibited an accelerated disease progression during treatment; this phenomenon was defined as accelerated disease progression following immune checkpoint blockade. Hyperprogression was first recognized at the 2016 Annual Meeting of the European Society of Medical Oncology (7). Lahmar et al (7) conducted a single-institution retrospective review of 89 patients with advanced NSCLC who received PD-1/PD-L1 inhibitors. Notably ~10% (9/89) of the patients exhibited rapid progression at the time of the first efficacy evaluation (>50%; expressed as a percentage of the tumor volume gained monthly), and the researchers characterized such progression as ‘paradoxical progressive disease’. The phenomenon of hyperprogression caused by immunotherapy attracted the attention of researchers when in a study by Champiat et al (8), at the beginning of 2017, the occurrence of hyperprogression in 9% (12/131) of patients receiving immunotherapy for >20 types of tumors and in 19% (>65) of older patients, was reported.

At present, there is no unified standard for HPD, and its evaluation criteria are mainly based on the following three parameters: Tumor growth rate, tumor growth kinetics (TGK) or time to treatment failure (TTF). Currently, the definition by Kato et al is generally accepted: i) TTF <2 months in immunotherapy; ii) tumor load is increased by >50% compared with the baseline; iii) cancer growth rate following immunotherapy is more than double the previous rate (9).

Due to different definition criteria and sample sizes of HPD, the frequency of HPD varies greatly among different cancer and study types. A previous study reported that the incidence of HPD associated with PD-1/PD-L1 inhibitors was 5.9-43.1%, with a combined incidence rate of 13.4% (10). In another study, patients with HPD had a worse prognosis, with a median overall survival (OS) of 3.4 months vs. 6.2 months without HPD (P=0.003) (11).

3. Pseudoprogression

Pseudoprogression refers to the imaging appearance of tumor progression followed by shrinkage or the emergence of new lesions. It typically refers to the process of tumor growth during immunotherapy and tumor shrinkage following reexamination. This process of ‘first increase and then decrease’ is called pseudoprogression.

Di Giacomo et al (12) reported pseudoprogression in a patient with melanoma treated with ipilimumab in 2009. In certain patients, melanoma volume first increased following ipilimumab administration. However, there was a delayed partial response with continuation of treatment. Anti-PD-1 antibody therapy has also been shown to induce pseudoprogression in patients with melanoma, with reported incidences ranging from 2.8-9.7% (12-16). Thereafter, pseudoprogression was also detected in other solid tumors, including NSCLC and squamous cell carcinoma of the head and neck, with frequencies from 1.3-6.9% (17-20). Pseudoprogression has also been observed in glioblastoma (21), renal cell carcinoma (22), chondrosarcoma (23), gastric cancer (24) and hepatocellular carcinoma (HCC) (25). Patients with pseudoprogression exhibited a significantly improved survival and better overall prognosis compared with patients with real progression (26). In case of pseudoprogression, stopping the drug midway may result in patients missing out on the optimal course of treatment or succumbing to disease. Therefore, it is crucial to accurately differentiate between pseudoprogression and HPD, and it may be necessary to conduct comprehensive and dynamic qualitative and quantitative analysis of different cell communities and factors at multiple time periods.

4. Potential influencing factors and mechanisms of HPD

Clinical factors and mechanisms. Age

Champiat et al (8) reported that HPD status was associated with age. Patients with HPD were older than those without HPD (P=0.007). That study also examined the impact of age on Response Evaluation Criteria in Solid Tumors (RECIST) response and found a statistically significant association (P=0.036) between age as a continuous variable and RECIST response. The results showed that 19% (7/36) of patients aged >65 years had HPD compared with 5% (5/95) of patients aged <64 years (Fisher's exact test; P=0.018). The fact that patients with HPD are older may be due to an altered immunological environment in older people, such as changes in the expression of T-cell costimulatory/co-inhibitory proteins or increased levels of inflammatory cytokines (27,28).


Kanjanapan et al (29) reported a higher incidence of HPD in women. Certain scholars maintain that this phenomenon may be due to the higher proportion of male patients smoking, more outdoor work and more ultraviolet exposure. These factors promote a higher immunogenicity and mutation load in male patients once they develop tumors, while the occurrence of tumors in female patients is higher due to adaptive immune escape. However, to better validate this, larger studies, including individual patient meta-analyses, are needed. A meta-analysis of 20 randomized controlled trials with a total of 11,351 patients treated with ICIs by Conforti et al (30) reported that men benefited from immunotherapy to a greater extent than women (hazard ratio for overall immunotherapy survival, 0.72 for men vs. 0.86 for women; P=0.0019), which suggests that there is a strong possibility of sex influence. On average, female adults have stronger innate and adaptive immune responses. In terms of adaptive immunity, women have higher CD4+ T-cell counts and higher CD4/CD8 ratios, while often exhibiting greater antibody responses, higher basal immunoglobulin levels, and higher B cell numbers than men. It is hypothesized that females develop more resistant tumors as an adaptation to their intrinsically stronger immune response in comparison with males (31). In addition, through a series of treatments on wild-type, estrogen receptor knockout (ERKO) and PD-1 KO mice, the results revealed that estrogen treatment increased intracellular PD-1 expression in FoxP3+ Tregs and PD-1, however FoxP3 expression was not sufficient to mediate Treg suppression, suggesting that a role for sex-hormone modulation of the PD-1/PDL1 pathway has emerged, albeit the published literature is limited to animal studies (32).

Local recurrence

In a retrospective study of 34 patients between September 2012 and 2015, Saada-Bouzid et al (33) determined that malignant progression occurred in 10 patients (29%), with at least local recurrence in 9 and distant in 1. Hyperprogression was significantly associated with local recurrence (TGK ratio <2:37% vs. TGK ratio ≥2:90%; P=0.008), but not with local or distant recurrence. Other studies also showed that HPD mostly occurred in the recurrence area following radiotherapy and chemotherapy, which supports this conclusion (6,34,35).


A multicenter retrospective study compared disease progression in patients with NSCLC receiving ICI or chemotherapy. A total of 59 patients developed HPD, of which 95% (56 cases) were caused by ICIs, while only 5% (3 cases) received chemotherapy. Patients with two or more metastases were more likely to develop HPD (62.5 vs. 42.6%; P=0.006); Compared with patients who developed progressive disease (PD), those who developed HPD within 6 weeks had a shorter survival time (median OS, 3.4 vs. 6.2 months; HR=2.18; P=0.003). This study showed that HPD is a poor prognostic factor for NSCLC, which is associated with a large tumor load. It also indicated that chemotherapy drugs can cause HPD, but the incidence was markedly lower than that of ICI (11). These may be due to the upregulation of VEGF and TGF-β by radiotherapy, leading to local TME transformation and HPD; however, the mechanisms behind this hypothesis remain unclear.

Number of metastases

Ferrara et al (11) revealed that PD-1/PD-L1 inhibitor-treated patients with advanced NSCLC were closely associated with the occurrence of HPD in patients with baseline metastasis (≥2), as compared with non-HPD patients. It is hypothesized that ≥2 metastatic foci at baseline may be a predictor of HPD following immunotherapy in patients with NSCLC. A previous study reported that HPD occurrence may be associated with structural characteristics of tumors, but the sample size of this study was limited, and its findings still require confirmation by a large number of prospective studies (36).

The association between clinically-related factors and poor tumor prognosis is presented in Table I.

Table I

Association between clinically-related factors and poor tumor prognosis.

Table I

Association between clinically-related factors and poor tumor prognosis.

Clinically-related factorsClinical manifestation/treament(Refs.)
AgeOlder (>65 years)(7,27,28)
Local recurrenceHigh local recurrence(6,33-35)
Number of metastases≥2(11,36)

[i] ICIs, immune checkpoint inhibitors.

Molecular markers

Current ICIs mainly target PD-L1, PD-1 and CTLA-4 molecules. But there are more than three immune checkpoints. When one immune checkpoint is inhibited by a drug, there may be compensatory activation of other checkpoints, leading to new immunosuppressive effects and rapid tumor growth.

A study involving a variety of tumors showed that mouse double minute 2 homolog (MDM2) gene amplification was linked to the occurrence of HPD (9). A study by Wang et al (37) demonstrated that MDM2 can inhibit the activity of p53, while interferon (IFN)-γ can increase the expression of MDM2 and further inhibit the activity of p53. Peng et al (38) showed that ICIs can increase the production of IFN-γ at the tumor site, suggesting that the IFN-γ-MDM2-p53 axis may be involved in mediating the development of HPD. In a mouse model study (39), PD-1-knockout mice that were infected with Mycobacterium tuberculosis produced excessive IFN-γ, resulting in mouse mortality. This study confirmed the association between PD-1 blockade and IFN-γ secretion from another angle, which is still lacking clinical evidence.

Singavi et al (40) published a study on MDM2/MDM4 amplification as a molecular marker for HPD population prediction and revealed that genetic variants on MDM2/MDM4, EGFR and 11q13 have links to HPD, however, their use as potential biomarkers of HPD warrants further investigation in larger cohorts.

A meeting abstract of the 19th American Society of Clinical Oncology showed that cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene deletion and MDM2 changes are closely linked to immune hyperplasia (41).

Since pretreatment predictors for patients with HPD are one of the key factors in managing patients receiving ICIs, genetic testing (liquid biopsy/tissue test) may be useful for clinical prediction. In the future, ICIs combined with MDM2/4 inhibitors may be a potential treatment strategy.

Concurrently, there are other research views. Kamada et al (42) found that patients with advanced gastric cancer without HPD also exhibited genetic changes, such as Erb-B2 receptor tyrosine kinase 2 (ERBB2) amplification, MDM2 amplification, tumor protein p53 (TP53) mutation, KRAS proto-oncogene, GTPase (KRAS) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation. Genetic alterations such as TP53 mutation, PIK3CA mutation, MDM2 amplification, ERBB2 amplification and KRAS amplification were also identified in patients with advanced gastric cancer who did not have HPD. This is an indication that these alterations may not be HPD-specific.

Understanding the role of different gene mutations in hyperprogression requires further study. Promising potential biomarkers for immunotherapy include liquid biopsies that identify free DNA or circulating tumor DNA (43). For instance, new directions in minimal residual disease techniques have linked chromosomal instability to a poor prognosis and resistance to treatment in a number of malignancies (44).

Immune microenvironment

The immune system plays a dual role in the body and may contribute to the development of cancer through both direct (induced DNA damage and free radical generation) and indirect (angiogenesis and tissue remodeling that promote production of growth factors and inflammatory matrix metalloproteinases) mechanisms.

The development of HPD may involve alterations in the tumor immune microenvironment, exacerbation of innate immune suppression, activation of oncogenic signals, and regulation of tumor-promoting cytokines (45). It has been hypothesized that PD-1 channel blocking could trigger a complex cascade, through mediating the immune system or directly accelerating a tumor growth inhibitory mechanism, altering the tumor immune microenvironment and leading to hyperprogression (46).

Tumor-infiltrating lymphocytes (TILs) are a type of infiltrating lymphocyte isolated from tumor tissue. TILs are a tumor antigen-specific CD4+ and CD8+ T-cell populations found in tumor tissue. The tumor suppressive effect of TILs in vivo is limited by CD4+ CD25+ Tregs, and the tumor killing activity can be restored following IL-2 stimulation in vitro. Following expansion, TILs can be used in adoptive tumor cell therapy in the clinic. Tregs are important suppressor cells and widely exist in TILs. Their function is similar to that of PD-1 signaling to suppress immune response and avoid autoimmune diseases. Tumors also recruit Tregs to their cells and use them to evade attack by the immune system (47). Previous evidence has suggested that high numbers of infiltrating Tregs in tumors are associated with poor prognosis (48). Adeegbe et al found that the number of Treg cells increased in the tumors of patients who experienced hyperprogression following the use of PD-1 inhibitors (48). Wen et al (49) revealed that the number of Treg mouse lymph nodes resistant to an anti-PD-1 antibody was significantly higher than that of mice sensitive to an anti-PD-1 antibody, suggesting that Tregs may be part of the resistance mechanism of anti-PD-1/PD-L1 antibodies. In addition, Oweida et al (50) observed that in a mouse model of squamous cell carcinoma of the head and neck, the accumulation of Tregs could promote tumor recurrence following anti-PD-L1 antibody treatment, in such a manner that the antitumor immunity generated by anti-PD-L1 antibody could not be sustained, that is, drug resistance was generated, and the antitumor immunity mediated by the anti-PD-L1 antibody could be restored following the depletion of Tregs. It was further demonstrated that Tregs were involved in anti-PD-L1 and PD-1 antibody resistance. In addition, Di Pilato et al (51) reported that the destruction of the Card9-BCL10-MALT1 signaling complex infiltrating Tregs in mouse tumors would cause them to lose their inhibitory function and exert antitumor effects through the secretion of IFN-γ, thus enhancing the efficacy of anti-PD-1/PD-L1 antibodies. Jacquelot et al (52) observed that the disruption of inducible nitric oxide synthase inhibited Treg activation in mouse tumors and could maintain the long-term antitumor effect of anti-PD-L1/PD-1 antibody. Tregs are major contributors to anti-PD-1/PD-L1 antibody resistance. The depletion of Tregs or disruption of their inhibitory function can improve the efficacy of anti-PD-1/PD-L1 antibodies. A study by Kumagai et al (53) also confirmed that PD-1 inhibitors are often effective when PD-1 is expressed at a high level in effector T cells and at a low level in Tregs in tumors. However, when the level of PD-1 expression on the effector T cells is low and the level of PD-1 expression on the Tregs is high, the use of PD-1 inhibitors is likely to be ineffective or lead to hyperprogression. Thus, Treg cells inhibit tumor regression, which is one of the mechanisms of hyperprogression in the TME; this is one of the challenges that needs to be resolved by TIL therapy.

At the same time, there is increasing awareness that changes in the TME, such as polarizing certain types of macrophages (such as CD163+ CD33+ PD-L1+ macrophages), could also lead to HPD (54).

Tumor-associated macrophages (TAMs) are important components of the microenvironment of solid tumors, differentiating along a spectrum from M1 tumor-killing macrophages to M2 tumor-promoting macrophages (55). TAMs in the hypoxic microenvironment of tumors are well recognized to confer resistance to a variety of anticancer therapies and to promote cancer recurrence (56). HPD can be classified as a drug-resistant disease.

Heterogeneity of the tumor environment has become a major research focus. There are significant differences in gene regulation and protein expression among different cancer types and tumor stages, which may be important factors leading to tumor hyperprogression. Wang et al (57) used single-cell RNA sequencing to dissect unique immune signals between lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD), the two main subtypes of NSCLC. Fatty acid-binding protein 4 (FABP4) macrophage was found to be the predominant component of macrophages in LUAD, but the predominant component of macrophages in LUSC was identified to be secreted phosphoprotein 1 (SPP1). The results demonstrated that macrophages and lymphocytes are important factors for the immuno-heterogeneity of lung cancer subtypes and revealed the unique function of the macrophage subcluster in the immuno-heterogeneity of lung cancer subtypes. Concurrently, a new lymphocyte-associated macrophage cluster was defined and it was labeled selenoprotein P (SELENOP)-macrophage. This subset expressed SELENOP, folate receptor beta, interleukin 32, CD3 delta subunit of T-cell receptor complex and leukotriene C4 synthase at high levels, indicating that they are closely associated with lymphocyte-related functions, and this subset was revealed to be involved in peptide metabolization, protein trafficking, and cytokine secretion and is critical for both LUAD and LUSC. These studies lay the foundation for the potential clinical development of new therapeutic targets in lung cancer in the TME.

Clever-1/stabilin-1 is widely found on lymphocytes, vascular endothelial cells and certain subtypes of M2 macrophages as a scavenger receptor and adhesion molecule. In patients with advanced colorectal cancer, patients with high expression of clever-1/stabilin-1 had a shorter survival and worse prognosis. A clinical study by Patten et al confirmed that clever-1 promotes tumor angiogenesis and regulates T-cell activity. The inhibition of clever-1 can increase the secretory activity of TAM proinflammatory cytokines and reactivate the antitumor activity of CD8+ T cells through antigen presentation, thereby overcoming the immunosuppressive TME (58).

Considering the complex microenvironment and highly heterogeneous characteristics of HCC, Liu et al (59) investigated the expression of various protein cells in the TME and revealed that the proportion of plasmacytoid dendritic and natural killer, T and B cells was significantly reduced, and the proportion of macrophages was significantly elevated in the tumor tissue. The level of expressed SPP1 and CD44 in HCC was also examined, and the findings indicated that the expression of SPP1 and CD44 in HCC tissues was markedly upregulated compared with that in normal tissues. Protein expression of CD44 as well as SPP1 was shown to be markedly higher in HCC than in healthy tissues by immunohistochemistry. Survival results showed that the prognosis of those with dual high expression of SPP1 and CD44 was poor, indicating the tumor-promoting roles of the SPP1/CD44 axis during HCC progression.

The leukocyte Ig-like receptor (LILR) family is one of the most important target groups for tumor progression. It has 13 members (including two pseudogenes) and is one of seven leukocyte immunoglobulin-like inhibitory receptors. LILRB4 is a type of suppressor receptor that has an important function in immunological checkpoint pathways. In patients with cancer, LILRB4 inhibits the proliferation of CD4+ T cells and promotes tumor growth and invasion by combining with its ligand CD166 and CD8+ CD28 T cells (60-63). Studies have revealed that LILRB4 plays a critical role in tyramine and in activating the tyramine receptor (64). In view of the role of LILRB4 in tumorigenesis, this discovery emphasizes the association between LILRB4 and tumors (65). Increasing evidence suggests that LILRB4 may be a regulator of tumor progression through the inhibition of the Akt signaling pathway. Thus, LILRB4 is considered a marker of malignancy. In solid tumors, LILRB2 can interact with major histocompatibility complex, class I, G, angiopoietin-like family, semaphorin 4A and CD1d-related ligands in the TME, causing myeloid cells to allow or promote tumor growth, and promote tumor immune escape. A previous study revealed that LILRB2 may act as a myeloid immune checkpoint. It reprograms tumor-associated myeloid cells and stimulates antitumor immunity (66). Several therapies targeting LILRB4 are currently in clinical development, including inhibitory antibodies, antibody-drug conjugate (ADC) and CAR-T cell therapies. With the in-depth study of LILRB4, a broader prospect in tumor application and hyperprogression research may be revealed for LILRB4.

Hyperprogression has been revealed to always be the result of a combination of complex factors. Li et al (67) suggested that the intersection of immune and tumor metabolic pathways drives cancer hyperprogression during immunotherapy. In animal models, T cell-derived IFN-γ has been revealed to promote tumor FGF2 signaling, thereby inhibiting PKM2 activity and reducing NAD+, resulting in sirt1-mediated decreased β-catenin deacetylation and enhanced β-catenin acetylation, thereby reprogramming tumor stemness (67). In preclinical models, targeting the IFNγ-PKM2-β-catenin axis was demonstrated to prevent HPD. Therefore, the interaction of core immunogenicity, metabolism, and oncogenic pathways through the IFNγ-PKM2-β-catenin cascade is the basis of immune checkpoint blockade-associated HPD (67). The association between the expression of various genes and poor tumor prognosis is revealed in Table II.

Table II

Association between the expression of various genes and poor tumor prognosis, identified using single-cell RNA sequencing.

Table II

Association between the expression of various genes and poor tumor prognosis, identified using single-cell RNA sequencing.

SubtypeExpressed by cells(Refs.)
Clever-1/stabilin-1Lymphocytes, vascular endothelial cells and certain subtypes of M2 macrophages(57)
SPP1 and CD44Tumor cells (hepatocellular carcinoma)(58)
LILRB4Antigen-presenting cells(59-64)
LILRB2Myeloid cells(65)

[i] FABP4, fatty acid-binding protein 4; Mφ, macrophages; SSP1, secreted phosphoprotein 1; LILR, leukocyte Ig-like receptor.

5. Conslusions

The clinically relevant factors, biomarkers and possible effects of the immune microenvironment on hyperprogression, described in the present review, have attracted increasing attention. HPD associated with ICI treatment usually predicts poor clinical prognosis (11). It is therefore necessary to explore predictors of HPD, with the aim of undertaking early treatment decisions without delays. The present review summarized the current findings of possible factors associated with hyperprogression. Clinically-relevant factors, such as individuals >65 years, women, greater local recurrence and number of metastases, as well as ICI treatment, indicate higher rates of hyperprogression. Biomarkers such as MDM2/MDM4, EGFR, CDKN2A/B, STK11, JAK3 and SOX9 are also closely associated with HPD, however the exact associations remains controversial. The major components of the immune microenvironment, such as FABP4 macrophages, SPP1 macrophages, clever-1/stabilin-1, SPP1, CD44, LILRB4 and LILRB2, all indicate the possibility of marked HPD. In cases where the cause of HPD is not clear, the characteristics of patients with accelerated progression compared with the clinical outcome may be investigated in reverse order, to identify the characteristics of patients with high risk of HPD, in order to reduce HPD-induced mortality. In recent years, the increasingly in-depth study of the immune microenvironment has provided novel insights into the abnormal hyperprogression of tumors, particularly the heterogeneity of various types of macrophages and marker proteins such as clever-1/stabilin-1 and LILBR family proteins in tumor progression. Therefore, it is considered that these factors may greatly influence the occurrence of tumor hyperprogression. Further studies with a greater number of cases and a more detailed genetic and protein analysis of patients with HPD need to be conducted urgently, to better understand the mechanism of HPD and thus reduce the incidence of HPD and improve the prognosis of patients with HPD. During immunotherapy, particularly during the first 6-8 weeks of immunotherapy, close attention should be paid to symptoms and physical changes.

In conclusion, hyperprogression is a relatively specific adverse immunotherapy-related phenomenon, not uncommon in immunotherapy, whose specific mechanism remains unknown. However, accelerated progression should not influence the selection of immunotherapy as a treatment option. Immunotherapy remains a promising antitumor strategy, and the discovery of hyperprogression should not prompt patients to abandon this treatment. Greater in-depth study of immunotherapy should be carried out, clarifying the occurrence and development mechanism of hyperprogression, in order to improve immunotherapy in the fight against tumors.


Not applicable.


Funding: The present study was supported by the Self-funded Project of Key Research and Development Plan of Xingtai City, China (grant no. 2021ZC178).

Availability of data and materials

Not applicable.

Authors' contributions

Literature collection and analysis were performed by RQ. XC is the corresponding author and contributed to the study conception and design. The first draft of the manuscript was written by RQ. LY, XZ, LH and PZ contibuted to the writing of previous versions of the manuscript and YW aided with language editing. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consents to participate

Not applicable.

Patient consents for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



Salama AK and Moschos SJ: Next steps in immuno-oncology: Enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies. Ann Oncol. 28:57–74. 2017.PubMed/NCBI View Article : Google Scholar


Sharon E: Can an immune checkpoint inhibitor (Sometimes) make things worse? Clin Cancer Res. 23:1879–1881. 2017.PubMed/NCBI View Article : Google Scholar


Hwang I, Park I, Yoon SK and Lee JL: Hyperprogressive disease in patients with urothelial carcinoma or renal cell carcinoma treated with PD-1/PD-L1 inhibitors. Clin Genitourin Cancer. 18:e122–e133. 2020.PubMed/NCBI View Article : Google Scholar


Kim CG, Kim KH, Pyo KH, Xin CF, Hong MH, Ahn BC, Kim Y, Choi SJ, Yoon HI, Lee JG, et al: Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol. 30:1104–1113. 2019.PubMed/NCBI View Article : Google Scholar


Petrioli R, Mazzei MA, Giorgi S, Cesqui E, Gentili F, Francini G, Volterrani L and Francini E: Hyperprogressive disease in advanced cancer patients treated with nivolumab: A case series study. Anticancer Drugs. 31:190–195. 2020.PubMed/NCBI View Article : Google Scholar


Chubachi S, Yasuda H, Irie H, Fukunaga K, Naoki K, Soejima K and Betsuyaku T: A case of non-small cell lung cancer with possible ‘disease flare’ on nivolumab treatment. Case Rep Oncol Med. 2016(1075641)2016.PubMed/NCBI View Article : Google Scholar


Lahmar J, Mezquita L, Koscielny S, Facchinetti F, Bluthgen MV, Adam J, Gazzah A, Remon J, Planchard D, Soria JC, et al: Immune checkpoint inhibitors (ICI) induce paradoxical progression in a subset of non-small cell lung cancer (NSCLC). Ann Oncol. 27 (Suppl 6)(VI423)2016.


Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, Chaput N, Eggermont A, Marabelle A, Soria JC and Ferté C: Hyperprogressive disease is a new pattern of progression in cancer patients treated by Anti-PD-1/PD-L1. Clin Cancer Res. 23:1920–1928. 2017.PubMed/NCBI View Article : Google Scholar


Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A and Kurzrock R: Hyperprogressors after immunotherapy: Analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 23:4242–4250. 2017.PubMed/NCBI View Article : Google Scholar


Park HJ, Kim KW, Won SE, Yoon S, Chae YK, Tirumani SH and Ramaiya NH: Definition, incidence, and challenges for assessment of hyperprogressive disease during cancer treatment with immune checkpoint inhibitors: A systematic review and meta-analysis. JAMA Netw Open. 4(e211136)2021.PubMed/NCBI View Article : Google Scholar


Ferrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, Mazieres J, Zalcman G, Brosseau S, Le Moulec S, et al: Hyperprogressive disease in patients with advanced non-small cell lung cancer treated With PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol. 4:1543–1552. 2018.PubMed/NCBI View Article : Google Scholar


Di Giacomo AM, Danielli R, Guidoboni M, Calabrò L, Carlucci D, Miracco C, Volterrani L, Mazzei MA, Biagioli M, Altomonte M and Maio M: Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: Clinical and immunological evidence from three patient cases. Cancer Immunol Immunother. 58:1297–1306. 2009.PubMed/NCBI View Article : Google Scholar


Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, et al: Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clin Cancer Res. 15:7412–7420. 2009.PubMed/NCBI View Article : Google Scholar


Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16:375–384. 2015.PubMed/NCBI View Article : Google Scholar


Long GV, Weber JS, Larkin J, Atkinson V, Grob JJ, Schadendorf D, Dummer R, Robert C, Márquez-Rodas I, McNeil C, et al: Nivolumab for patients with advanced melanoma treated beyond progression: Analysis of 2 phase 3 clinical trials. JAMA Oncol. 3:1511–1519. 2017.PubMed/NCBI View Article : Google Scholar


Nishino M, Giobbie-Hurder A, Manos MP, Bailey N, Buchbinder EI, Ott PA, Ramaiya NH and Hodi FS: Immune-Related tumor response dynamics in melanoma patients treated with pembrolizumab: Identifying markers for clinical outcome and treatment decisions. Clin Cancer Res. 23:4671–4679. 2017.PubMed/NCBI View Article : Google Scholar


Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, et al: Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol. 33:1430–1437. 2015.PubMed/NCBI View Article : Google Scholar


Nishino M, Ramaiya NH, Chambers ES, Adeni AE, Hatabu H, Jänne PA, Hodi FS and Awad MM: Immune-related response assessment during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients. J Immunother Cancer. 4(84)2016.PubMed/NCBI View Article : Google Scholar


Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 373:123–135. 2015.PubMed/NCBI View Article : Google Scholar


Haddad R, Concha-Benavente F, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Kasper S, Vokes EE, Worden F, et al: Nivolumab treatment beyond RECIST-defined progression in recurrent or metastatic squamous cell carcinoma of the head and neck in CheckMate 141: A subgroup analysis of a randomized phase 3 clinical trial. Cancer. 125:3208–3218. 2019.PubMed/NCBI View Article : Google Scholar


Aquino D, Gioppo A, Finocchiaro G, Bruzzone MG and Cuccarini V: MRI in glioma immunotherapy: Evidence, pitfalls, and perspectives. J Immunol Res. 2017(5813951)2017.PubMed/NCBI View Article : Google Scholar


Elias R, Kapur P, Pedrosa I and Brugarolas J: Renal cell carcinoma pseudoprogression with clinical deterioration: To hospice and back. Clin Genitourin Cancer. 16:485–488. 2018.PubMed/NCBI View Article : Google Scholar


Wagner MJ, Ricciotti RW, Mantilla J, Loggers ET, Pollack SM and Cranmer LD: Response to PD1 inhibition in conventional chondrosarcoma. J Immunother Cancer. 6(94)2018.PubMed/NCBI View Article : Google Scholar


Michalarea V, Fontana E, Garces AI, Williams A, Smyth EC, Picchia S, Rao S, Chau I, Cunningham D and Bali MA: Pseudoprogression on treatment with immune-checkpoint inhibitors in patients with gastrointestinal malignancies: Case series and short literature review. Curr Probl Cancer. 43:487–494. 2019.PubMed/NCBI View Article : Google Scholar


Mamdani H, Wu H, O'Neil BH and Sehdev A: Excellent response to Anti-PD-1 therapy in a patient with hepatocellular carcinoma: Case report and review of literature. Discov Med. 23:331–336. 2017.PubMed/NCBI


Basler L, Gabryś HS, Hogan SA, Pavic M, Bogowicz M, Vuong D, Tanadini-Lang S, Förster R, Kudura K, Huellner MW, et al: Radiomics, tumor volume, and blood biomarkers for early prediction of pseudoprogression in patients with metastatic melanoma treated with immune checkpoint inhibition. Clin Cancer Res. 26:4414–4425. 2020.PubMed/NCBI View Article : Google Scholar


Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G and Fulop T: Innate immunosenescence: Effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 24:331–341. 2012.PubMed/NCBI View Article : Google Scholar


Goronzy JJ and Weyand CM: Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 14:428–436. 2013.PubMed/NCBI View Article : Google Scholar


Kanjanapan Y, Day D, Wang L, Al-Sawaihey H, Abbas E, Namini A, Siu LL, Hansen A, Razak AA, Spreafico A, et al: Hyperprogressive disease in early-phase immunotherapy trials: Clinical predictors and association with immune-related toxicities. Cancer. 125:1341–1349. 2019.PubMed/NCBI View Article : Google Scholar


Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, Gelber RD and Goldhirsch A: Cancer immunotherapy efficacy and patients' sex: A systematic review and meta-analysis. Lancet Oncol. 19:737–746. 2018.PubMed/NCBI View Article : Google Scholar


Conforti F, Pala L and Goldhirsch A: Different effectiveness of anticancer immunotherapy in men and women relies on sex-dimorphism of the immune system. Oncotarget. 9:31167–31168. 2018.PubMed/NCBI View Article : Google Scholar


Polanczyk MJ, Hopke C, Vandenbark AA and Offner H: Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol. 19:337–343. 2007.PubMed/NCBI View Article : Google Scholar


Saâda-Bouzid E, Defaucheux C, Karabajakian A, Coloma VP, Servois V, Paoletti X, Even C, Fayette J, Guigay J, Loirat D, et al: Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 28:1605–1611. 2017.PubMed/NCBI View Article : Google Scholar


Yoshida T, Furuta H and Hida T: Risk of tumor flare after nivolumab treatment in patients with irradiated field recurrence. Med Oncol. 34(34)2017.PubMed/NCBI View Article : Google Scholar


Ogata T, Satake H, Ogata M, Hatachi Y and Yasui H: Hyperprogressive Disease in the irradiation field after a single dose of nivolumab for gastric cancer: A case report. Case Rep Oncol. 11:143–150. 2018.PubMed/NCBI View Article : Google Scholar


Sasaki A, Nakamura Y, Mishima S, Kawazoe A, Kuboki Y, Bando H, Kojima T, Doi T, Ohtsu A, Yoshino T, et al: Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer. Gastric Cancer. 22:793–802. 2019.PubMed/NCBI View Article : Google Scholar


Wang S, Zhao Y, Aguilar A, Bernard D and Yang CY: Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: Progress and challenges. Cold Spring Harb Perspect Med. 7(a026245)2017.PubMed/NCBI View Article : Google Scholar


Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L and Hwu P: PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 72:5209–5218. 2012.PubMed/NCBI View Article : Google Scholar


Sakai S, Kauffman KD, Sallin MA, Sharpe AH, Young HA, Ganusov VV and Barber DL: CD4 T Cell-Derived IFN-γ plays a minimal role in control of pulmonary mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease. PLoS Pathog. 12(e1005667)2016.PubMed/NCBI View Article : Google Scholar


Singavi AK, Menon S, Kilari D, Alqwasmi A, Ritch PS, Thomas JP, Martin AL, Oxencis C, Ali SM and George B: 1140PDPredictive biomarkers for hyper-progression (HP) in response to immune checkpoint inhibitors (ICI)-analysis of somatic alterations (SAs). Ann Oncol. 28 (Suppl 5):2017.


Giusti R, Mazzotta M, Filetti M, Marinelli D, Di Napoli A, Scarpino S, Scafetta G, Mei M, Vecchione A, Ruco L and Marchetti P: CDKN2A/B gene loss and MDM2 alteration as a potential molecular signature for hyperprogressive disease in advanced NSCLC: A next-generation-sequencing approach. J Clin Oncol. 37(e20628)2019.


Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, et al: PD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA. 116:9999–10008. 2019.PubMed/NCBI View Article : Google Scholar


Li L, Zhang J, Jiang X and Li Q: Promising clinical application of ctDNA in evaluating immunotherapy efficacy. Am J Cancer Res. 8:1947–1956. 2018.PubMed/NCBI


McClelland SE: Role of chromosomal instability in cancer progression. Endocr Relat Cancer. 24:T23–T31. 2017.PubMed/NCBI View Article : Google Scholar


Han XJ, Alu A, Xiao YN, Wei YQ and Wei XW: Hyperprogression: A novel response pattern under immunotherapy. Clin Transl Med. 10(e167)2020.PubMed/NCBI View Article : Google Scholar


Boussiotis VA: Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 375:1767–1778. 2016.PubMed/NCBI View Article : Google Scholar


Rosenberg SA, Spiess P and Lafreniere R: A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 233:1318–1321. 1986.PubMed/NCBI View Article : Google Scholar


Adeegbe DO and Nishikawa H: Natural and induced T regulatory cells in cancer. Front Immunol. 4(190)2013.PubMed/NCBI View Article : Google Scholar


Wen L, Lu H, Li Q, Wen S, Wang D, Wang X, Fang J, Cui J, Cheng B and Wang Z: Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis. J Exp Clin Cancer Res. 38(299)2019.PubMed/NCBI View Article : Google Scholar


Oweida A, Hararah MK, Phan A, Binder D, Bhatia S, Lennon S, Bukkapatnam S, Van Court B, Uyanga N, Darragh L, et al: Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration. Clin Cancer Res. 24:5368–5380. 2018.PubMed/NCBI View Article : Google Scholar


Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, Usmani SM, Misale S, Zappulli V, Carrizosa E, et al: Targeting the CBM complex causes T(reg) cells to prime tumours for immune checkpoint therapy. Nature. 570:112–116. 2019.PubMed/NCBI View Article : Google Scholar


Jacquelot N, Yamazaki T, Roberti MP, Duong CPM, Andrews MC, Verlingue L, Ferrere G, Becharef S, Vétizou M, Daillère R, et al: Sustained type I interferon signaling as a mechanism of resistance to PD-1 blockade. Cell Res. 29:846–861. 2019.PubMed/NCBI View Article : Google Scholar


Kumagai S, Togashi Y, Kamada T, Sugiyama E, Nishinakamura H, Takeuchi Y, Vitaly K, Itahashi K, Maeda Y, Matsui S, et al: The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol. 21:1346–1358. 2020.PubMed/NCBI View Article : Google Scholar


Lo Russo G, Moro M, Sommariva M, Cancila V, Boeri M, Centonze G, Ferro S, Ganzinelli M, Gasparini P, Huber V, et al: Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res. 25:989–999. 2019.PubMed/NCBI View Article : Google Scholar


Movahedi K, Laoui D, Gysemans C, Baeten M, Stangé G, Van den Bossche J, Mack M, Pipeleers D, In't Veld P, De Baetselier P and Van Ginderachter JA: Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 70:5728–5739. 2010.PubMed/NCBI View Article : Google Scholar


Henze AT and Mazzone M: The impact of hypoxia on tumor-associated macrophages. J Clin Invest. 126:3672–3679. 2016.PubMed/NCBI View Article : Google Scholar


Wang C, Yu Q, Song T, Wang Z, Song L, Yang Y, Shao J, Li J, Ni Y, Chao N, et al: The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing. Signal Transduct Target Ther. 7(289)2022.PubMed/NCBI View Article : Google Scholar


Patten DA and Shetty S: The role of stabilin-1 in lymphocyte trafficking and macrophage scavenging in the liver microenvironment. Biomolecules. 9(283)2019.PubMed/NCBI View Article : Google Scholar


Liu Y, Zhang L, Ju X, Wang S and Qie J: Single-Cell transcriptomic analysis reveals macrophage-tumor crosstalk in hepatocellular carcinoma. Front Immunol. 13(955390)2022.PubMed/NCBI View Article : Google Scholar


Xu Z, Chang CC, Li M, Zhang QY, Vasilescu EM, D'Agati V, Floratos A, Vlad G and Suciu-Foca N: ILT3.Fc-CD166 interaction induces inactivation of p70 S6 kinase and inhibits tumor cell growth. J Immunol. 200:1207–1219. 2018.PubMed/NCBI View Article : Google Scholar


Willoughby JE, Kerr JP, Rogel A, Taraban VY, Buchan SL, Johnson PW and Al-Shamkhani A: Differential impact of CD27 and 4-1BB costimulation on effector and memory CD8 T cell generation following peptide immunization. J Immunol. 193:244–251. 2014.PubMed/NCBI View Article : Google Scholar


Chen L, Xu Z, Chang C, Ho S, Liu Z, Vlad G, Cortesini R, Clynes RA, Luo Y and Suciu-Foca N: Allospecific CD8 T suppressor cells induced by multiple MLC stimulation or priming in the presence of ILT3.Fc have similar gene expression profiles. Hum Immunol. 75:190–196. 2014.PubMed/NCBI View Article : Google Scholar


Vlad G and Suciu-Foca N: Induction of antigen-specific human T suppressor cells by membrane and soluble ILT3. Exp Mol Pathol. 93:294–301. 2012.PubMed/NCBI View Article : Google Scholar


Braza MKE, Gazmen JDN, Yu ET and Nellas RB: Ligand-Induced conformational dynamics of a tyramine receptor from sitophilus oryzae. Sci Rep. 9(16275)2019.PubMed/NCBI View Article : Google Scholar


Mukherjee A, Acharya S, Purkait K, Chakraborty K, Bhattacharjee A and Mukherjee A: Effect of N,N Coordination and Ru(II) Halide Bond in Enhancing Selective Toxicity of a Tyramine-Based Ru(II) (p-Cymene) Complex. Inorg Chem. 59:6581–6594. 2020.PubMed/NCBI View Article : Google Scholar


Chen HM, van der Touw W, Wang YS, Kang K, Mai S, Zhang J, Alsina-Beauchamp D, Duty JA, Mungamuri SK, Zhang B, et al: Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. J Clin Invest. 128:5647–5662. 2018.PubMed/NCBI View Article : Google Scholar


Li G, Choi JE, Kryczek I, Sun Y, Liao P, Li S, Wei S, Grove S, Vatan L, Nelson R, et al: Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy. Cancer Cell. 41:304–322.e7. 2023.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

Volume 20 Issue 1

Print ISSN: 2049-9450
Online ISSN:2049-9469

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Qi R, Yang L, Zhao X, Huo L, Wang Y, Zhang P and Chen X: Progress in the research of immunotherapy‑related hyperprogression (Review). Mol Clin Oncol 20: 3, 2024
Qi, R., Yang, L., Zhao, X., Huo, L., Wang, Y., Zhang, P., & Chen, X. (2024). Progress in the research of immunotherapy‑related hyperprogression (Review). Molecular and Clinical Oncology, 20, 3.
Qi, R., Yang, L., Zhao, X., Huo, L., Wang, Y., Zhang, P., Chen, X."Progress in the research of immunotherapy‑related hyperprogression (Review)". Molecular and Clinical Oncology 20.1 (2024): 3.
Qi, R., Yang, L., Zhao, X., Huo, L., Wang, Y., Zhang, P., Chen, X."Progress in the research of immunotherapy‑related hyperprogression (Review)". Molecular and Clinical Oncology 20, no. 1 (2024): 3.