Cancer ranks as one of the most fatal diseases, with its incidence rapidly growing, and remains a major public health problem in the world (1, 2). Although a variety of treatment methods have been applied to cancer, including surgery, chemotherapy, radiotherapy, and targeted therapies over the past few decades, the prognosis remains unsatisfactory (2). Fortunately, the advent of immunotherapy has revolutionized cancer treatment and has been the cornerstone of success in treating several malignancies (3, 4). Immune checkpoint inhibitors (ICIs) have become a novel and effective therapeutic strategy and the mainstay of treatment for many cancers (5, 6). Despite proven clinical efficacy, a significant proportion of patients do not respond to immunotherapy. A subset of patients who experienced an extremely rapid boost in tumor volume during the treatment with ICIs that far exceeded the pretreatment growth rate, which was defined as hyperprogressive disease (7). Patients with HPD often showed both shorter progression-free survival and overall survival than patients with natural progressive disease (PD) and loss of eligibility for subsequent systemic treatments owing to clinical deterioration (8). Thus, early identification of HPD is very crucial. Multiple studies have reported possible predictive factors of HPD, including serum lactate dehydrogenase above the upper normal limit, the presence of more than two metastatic sites, liver metastases, programmed cell death ligand-1 (PD-L1) positivity, a Royal Marsden Hospital prognostic score of 2 or above, and an Eastern Cooperative Oncology Group Performance Score ≥ 2 (9, 10). Apart from these factors, numerous studies have been conducted to evaluate the neutrophil-to-lymphocyte ratio (NLR) for HPD (11–28). However, these studies have produced different results, and many do not support each other. The predictive value of the NLR for HPD remains controversial. Thus, we performed a systematic review and meta-analysis on this topic to identify the predictive value of HPD.

HPD is a paradoxical acceleration of tumor growth phenomenon, which often leads to early death commonly in the first 2 months of treatment with ICIs (32). The incidence of HPD after treatment with ICIs ranged from 1.2% to 43.1% (10), while in our meta-analysis, the pooled incidence of HPD varied from 6.3% to 35.6%, which may be related to the inclusion of different tumor types and different assessment methods for HPD in previous studies (33). Multiple factors are thought to contribute to the occurrence of HPD, including clinical features, genetic features, and tumor immune microenvironment characteristics (9, 10, 34, 35). The mechanism of HPD occurrence and the exact causes are poorly understood. In some preclinical models, ICI causes HPD. Recently, Li et al. found a triple-high gene signature score (IFNγ–FGF2–β-catenin) associated with HPD in patients and revealed crosstalk between metabolic, immunogenic, and oncogenic pathways underlying HPD associated with immunotherapy (36).

HPD is not unique to immunotherapy (37), the incidence of which will increase. It also occurs in conventional chemotherapy and targeted therapies. The overall survival of patients with HPD was significantly shortened, suggesting that once HPD occurs, it can seriously affect the prognosis of patients (38, 39). Although some researchers caution that HPD represents the natural disease course of a subset of patients with aggressive cancers (40–42), most studies now support that patients with HPD had a worse outcome than patients with so-called “conventional” progression (43). Once these patients develop HPD after receiving immunotherapy, they are often deprived of their chance to receive subsequent treatment (44). It is a particular phenomenon that patients cannot benefit from immunotherapy because of the lack of prediction methods (45). A recent study identifies SAA1 and specific metabolomic signatures as potential predictive biomarkers for HPD in patients undergoing immunotherapy across various cancers (46). However, metabolic biomarkers are preferred for the dynamic monitoring of HPD due to their susceptibility to fluctuations caused by metabolic disorders; they will take a long time and may delay HPD diagnosis. Furthermore, many immunohistochemistry specimens cannot be obtained due to various reasons. In this scenario, it is important to identify HPD biomarkers for selection before ICI therapy.

The NLR is defined as the absolute neutrophil count divided by the absolute lymphocyte count. It is a practical, easy acquisition, and low-cost marker of the immune system’s inflammatory response (47). In the oncological context, an elevated NLR is often observed in individuals presenting with advanced or aggressive forms of cancer (48). This may be due to tumor cells secreting granulocyte colony-stimulating factor (G-CSF) and/or granulocyte monocyte colony-stimulating factor (GM-CSF), which not only are direct growth factors for tumor cells, but also may lead to increased NLR in patients. Thus, bone marrow hematopoiesis shifts from the lymphocyte lineage to the granulocyte lineage (49, 50). Accumulating evidence has revealed that the NLR is associated with tumor malignant degree invasive biological features and the efficacy of immunotherapy (51). In the era of immunotherapy, the NLR often represents a significant, feasible prognostic factor (52, 53). An evidence synthesis from 30 meta-analyses indicated that the NLR is associated with poor outcomes in patients with cancer receiving immunotherapy (54). There may be a certain correlation, and a similar situation exists in HPD. An increasing number of researchers have speculated that the NLR may be a biomarker for predicting the occurrence of HPD. However, inconsistent results have emerged from multiple studies. For example, original cohort studies conducted by Petrova et al. (14), Karabajakian et al. (19), Kim et al. (21), Takahashi et al. (55), Milla et al. (56), and Maesaka et al. (57) have concluded that the risk of HPD occurrence will increase with elevated NLR, which can be used as a marker for HPD. Our study was in line with this conclusion. We found that patients with high NLR had a higher probability of developing HPD after ICI treatment, and the difference was statistically significant (OR = 0.65; 95% CI: 0.46 to 0.891; p = 0.01). However, the other subset of original cohort studies had been conducted by Champiat et al. (7), Kim et al. (8), Zhang et al. (12), Xiao et al. (13), Chen et al. (18), Ferrara et al. (20), Wang et al. (22), Park et al. (23), and Choi et al. (58), and their colleagues showed that elevated NLR was not significantly associated with the occurrence of HPD. Meanwhile, two meta-analyses had drawn similar conclusions (10, 59). Numerous factors may account for these results. First, some studies included a small sample size. Second, different researchers included different cancer types; for instance, Liu et al. only included solid tumors, and we added hematologic tumors to our study. Last but not least, there is currently no consensus cutoff value of the NLR for predicting the occurrence of HPD. Future studies with larger sample sizes and an optimal cutoff value of the NLR to validate the results of this study are needed.

The exact mechanism between an elevated NLR and HPD has yet to be elucidated. The possible mechanisms are as follows: first, tumor cells can induce bone marrow to produce more neutrophils into the blood and promote tumor progression through multiple immunosuppressive pathways. Neutrophils can interact with other immune cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), to create an immunosuppressive environment. These interactions can lead to the polarization of macrophages towards an M2 phenotype, which is immunosuppressive and supports tumor progression (60). Second, a high NLR often indicates a greater presence of neutrophils, which induce angiogenesis, tumor growth, and metastasis by secreting tumor growth factors, cytokines, and chemokines, such as transforming growth factor P (TGP-P), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), and stromal metalloproteinases (61–63). Third, neutrophils are part of the innate immune system and can contribute to an inflammatory environment that supports tumor progression. An elevated NLR may signal a pro-inflammatory state within the tumor (64). Additionally, neutrophils have been shown to participate in immune evasion strategies employed by tumors. They can release factors that inhibit T-cell function, such as arginase and reactive oxygen species (ROS), which can suppress the activity of cytotoxic T cells that are essential for antitumor immunity (65, 66). Last but not the least, in the latest study, Ng et al. revealed that tumor-reprogrammed neutrophils converge immature and mature neutrophils to a terminally differentiated T3 state, which promotes angiogenesis by localizing in hypoxic–glycolytic niches and enhancing blood vessel formation in the tumor microenvironment, thus promoting the occurrence and development of tumors (67). At the same time, lymphocytes play a vital role in antitumor immunity and are the leading performers of immune functions in the antitumor process. T lymphocytes can recognize and kill tumor cells, thus inhibiting tumor proliferation. Lymphocytes also participate in antitumor immunity by releasing cytokines (68). Since ICIs depend on the suppressive signaling function of T lymphocytes, a decrease in lymphocyte counts decreases the antitumor immune response and affects the efficacy of ICIs. Increased lymphocyte infiltration in the tumor immune microenvironment is associated with better prognosis and immunotherapy efficacy (69, 70).While the number of lymphocytes is insufficient, it leads to an inadequate immune response to the tumor, which promotes tumor progression and metastasis. Increased neutrophils suggest a poor prognosis, while tumor-associated lymphocytes are associated with a better prognosis. The NLR can measure the immune system’s inflammatory state, reflecting the balance between tumor protection and destruction. Therefore, it is inferred that the NLR can be used as a predictor for the occurrence of HPD.

Admittedly, there are several limitations in our study. The meta-analysis included 17 studies, all of which were retrospective studies, and the type of studies in this category was somewhat confounded with bias. It is insufficient to reveal a causal relationship between specific indicators or clinical features and HPD, yet such high-quality prospective studies examining the interaction of these indicators with HPD events are still lacking. At the same time, the assessment criteria for HPD, tumor growth kinetic indicators, and the definition of HPD vary, which may affect the consolidation of results across studies and lead to selection and reporting bias. Thus, we should develop and validate a standardized HPD definition as early as possible in further studies and conduct more high-quality, large-scale multi-center studies to confirm the predictive value of the NLR for the occurrence of HPD and provide strong evidence for clinical decision-making.

Given the limitations of ICI due to HPD incidence, there is an urgent need for reliable biomarkers to predict the occurrence of HPD and the efficacy of ICI (71). Although radiomic features can help identify the features of HPD after immunotherapy has been reported (72), the definition of HPD based on TGR ratio or TKR ratio may preclude its clinical use in many patients due to the lack of pre-baseline imaging data. Such complexity may be the barrier in incorporating the HPD concept into clinical practice. It is imperative for us to search a simpler and more routinely available tool to assess HPD. To a certain extent, the NLR can compensate for the deficiency of imaging examinations, achieve dynamic monitoring, and identify HPD early and accurately, which may reduce the incidence of HPD. For patients who have developed HPD, the combination with other ICIs, radiotherapy, chemotherapy, and targeted therapies may provide a synergistic antitumor effect and become a reliable approach to treating HPD. The study of Park and colleagues suggested that patients who experienced HPD with ICIs should not be excluded from the subsequent salvage chemotherapy treatments, owing to potentially enriched therapeutic benefits of post-ICI chemotherapy in R/M-HNSCC (23). Clinical studies of multiple combination treatment options are currently being explored, and the results of these studies are expected to bring new hope for the clinical treatment of HPD.

In summary, this systematic review and meta-analysis revealed that the NLR might be an easy, low-cost, and readily available method and biomarker to predict the occurrence of HPD. It can be used to identify HPD early and take measures to reduce the incidence of HPD. The result is of great importance for evidence-based clinical decision-making in oncology practice, where immunotherapy has become a mainstay of cancer medical therapy. Therefore, before patients receive ICI therapy, combining routine clinical examinations with an evaluation of NLR is needed to provide them with a safe and optimal treatment option.