Currently, the risk factors for HPD remain unclear. Several studies have identified specific risk factors associated with HPD. Kanjanapan et al. (18) found that HPD occurrence was significantly associated with female gender (P = 0.01), but showed no correlation with age, performance status, or tumor type. However, studies (19, 20) indicated that advanced age (>65 years), female gender, and the presence of more than two metastatic lesions are high-risk factors for HPD development. Additionally, Borghaei (21) suggested that age ≥75 years is a significant risk factor. Sasaki et al. (14) identified a positive correlation between absolute neutrophil count and elevated C-reactive protein levels with the development of HPD. Another study (22) suggested that elevated lactate dehydrogenase (LDH) levels above the normal upper limit are associated with HPD occurrence. A systematic review (23) revealed a significant association between neutrophil-to-lymphocyte ratio (NLR) and the risk of HPD. Castello et al. (24) found that an NLR > 4.125 serves as an independent predictor of HPD, OS and PFS in patients undergoing immunotherapy. Dovedi et al. (25) observed that low-dose fractionated radiotherapy may upregulate PD-L1 expression, partially counteracting the effects of immunosuppressants and increasing the risk of HPD. Furthermore, research (26) demonstrated that early liquid biopsy monitoring of cfDNA is effective for early prediction of HPD. The incidence of HPD varies among patients with different malignant tumors treated with PD-1 inhibitors and is associated with certain clinicopathological features and poor prognosis. Chen et al. (27) found that tumor markers, particularly CA-19-9, may serve as early predictors of HPD. However, in our report, the patient’s CA19–9 levels remained within the normal range, whereas CEA showed a significant and sustained increase, which may represent a risk factor for predicting HPD. Although several risk factors associated with HPD have been identified, conclusions across studies are not entirely consistent. Therefore, these risk factors lack specificity, and future research is needed to identify independent predictors of HPD.

The molecular mechanisms underlying HPD remain poorly understood and may involve either single-gene mutations or concurrent multiple gene mutations. These gene mutations induce alterations in the TME, leading to HPD development. MDM2 mutations play a critical role in HPD occurrence. Kato et al. (12) observed that patients with MDM2 amplification experienced further amplification during immunotherapy, resulting in impaired p53 protein function and subsequent HPD development. Singavi et al. (28) reported an HPD incidence as high as 66% in patients exhibiting MDM2/MDM4 amplification following ICI therapy. EGFR amplification leads to autophosphorylation of receptor tyrosine kinases, triggering downstream signaling pathways that regulate cell proliferation, differentiation, and survival, and is implicated in the pathogenesis of various human cancers. Chubachi et al. (11) documented a case of lung adenocarcinoma harboring an EGFR mutation that developed HPD following ICI treatment. Singavi et al. (28) confirmed an HPD incidence of 50% among patients with EGFR amplification. Kato et al. (12) found that among ten patients with EGFR mutations, eight exhibited treatment failure within two months, and two developed HPD. A study (29) first identified MET copy number as a key factor influencing the response of lung cancer patients to ICIs, with higher MET copy numbers correlating with poorer prognosis. Combined treatment with MET inhibitors and PD-1 inhibitors can enhance anti-tumor immunity and promote tumor regression. Collectively, these studies indicate that MET amplification contributes to tumor immune resistance and progression, with higher MET copy numbers increasing this likelihood. FGFR signaling is dysregulated in numerous human cancers and is considered a potential uncontrolled therapeutic target. Singavi et al. (28) reported that specific genes on human chromosome 11q13, including CCND1, FGF3, FGF4, and FGF19, were amplified in 75% of five HPD patients, suggesting a potential association with HPD. Inhibition of FGFR phosphorylation suppresses downstream signaling in FGFR-dysregulated tumor cell lines, demonstrating broad-spectrum anti-tumor activity across various FGFR-mutated cancers, including gastric, lung, multiple myeloma, bladder, endometrial, and breast cancers (30). Study (31) found that increased FGFR-1 expression is associated with oral tongue squamous cell carcinoma (OTSCC) and correlates with metastasis and poor outcomes in OTSCC patients. Regulatory T cell (T-reg) exert negative regulatory effects in tumor immunotherapy, with immune checkpoints such as CTLA-4 and PD-1 selectively overexpressed on TME-resident T-reg cells. Research (32) demonstrated that tumor-infiltrating T-reg cells are abundant and highly suppressive in most GC patients, exhibiting PD-1 expression levels far exceeding those of circulating T-reg cells. Comparative analysis of GC tissue samples before and after ICI therapy revealed a significant increase in tumor-infiltrating T-reg cells in HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ effector T-reg (eT-reg) cells are highly activated, and PD-1 blockade significantly enhances their suppressive activity in vitro.

Moreover, activation of certain oncogenic signaling pathways following immune checkpoint blockade, along with subsequent activation of cancer-promoting pathways, induces changes in the TME. This leads to upregulation of PD-1, PD-L1, and CTLA-4 expression, which adversely affects anti-tumor immunity and represents a key factor in the development of HPD. ICIs, by blocking the PD-1/PD-L1 pathway, disrupt immune homeostasis and alter the TME, causing a significant increase in T-reg and immunosuppressive tumor infiltration, ultimately promoting tumor immune evasion and accelerated growth. Besides directly inducing proliferation and activation of T-reg, ICIs can also upregulate PD-L1 expression, further enhancing T-reg expansion, thereby suppressing anti-tumor immunity and facilitating HPD development (33). Boussiotis et al. (34) reported that the PD-1/PD-L1 axis inhibits PLC-γ and RAS activation, subsequently suppressing Mek/Erk MAPK pathway activity, which paradoxically promotes tumor cell proliferation and invasion. Although blocking the PD-1/PD-L1 pathway can reactivate anti-tumor T cells, it also upregulates PD-1 expression, targeting PTEN-dependent signaling and enhancing transcription of oncogenic pathways such as PI3K/AKT and TGF-β, thereby contributing to HPD (35). Xiong et al. (36) found that tumor suppressor genes such as TSC2 negatively regulate signaling pathways controlling cell growth and proliferation; the pY1611S mutation located within the Rap/RanGAP domain of TSC2 may lead to functional loss, resulting in deregulated tumor cell proliferation following ICI treatment. This is associated with suppression of the TP53 pathway, which modulates expression of immune targets—including antigen-presenting cells (APCs), natural killer (NK) cells, and T-reg—in the tumor microenvironment via downstream TP53 signaling, while concurrently activating MYC, CCND1, and VEGF pathways, leading to tumor immune evasion and promotion of HPD (38). Known as the guardian of the genome, p53 is a tumor suppressor that regulates cellular functions through diverse mechanisms including DNA repair, apoptosis, cell cycle arrest, senescence, metabolism, and autophagy; mutations in p53 lead to uncontrolled cell proliferation. Studies indicate a link between the IFN-γ–MDM2–p53 axis and HPD development. ICIs induce upregulation of IFN-γ in the TME, activating the JAK-STAT pathway and enhancing IRF-8 expression, which binds to the MDM2 promoter to induce MDM2 expression, ultimately suppressing p53 activity and accelerating tumor progression (37). MDM2 amplification coexists with multiple gene mutations and promotes activation of several oncogenic signaling pathways. Among 3,650 patients with MDM2 amplification, 25.37% exhibited mutations in PI3K pathway-related genes, while 24.93% had TP53 mutations. Additionally, 23.64% of patients harbored MAPK pathway-related mutations along with TP53 mutations at a frequency of 24.93%. These co-mutations may be associated with HPD occurrence. MDM2 amplification has been shown to trigger functional autoimmune responses, thereby promoting the expansion of functional autologous tumor-specific T cells (39). One of the genes activated by p53 is MDM2, which induces p53 degradation; however, inhibitory drugs targeting MDM2 can reduce p53 degradation (39). Kato et al. (12) hypothesized that the signaling cascade triggered by MDM2 gene amplification promotes HPD, or that certain genes co-amplified with the MDM2 amplicon interact to mediate HPD. EGFR amplification enhances STAT expression, activating the IFN-γ-JAK1/2-STAT1-mediated PD-L1 axis, which upregulates PD-L1 expression and induces cytotoxic T lymphocyte (CTL) dysfunction, leading to host immune evasion (40). Okita et al. (41) demonstrated that the PI3K/AKT and JAK/STAT signaling pathways cooperatively regulate PD-L1 expression. Furthermore, EGFR mutations may regulate PD-L1 expression through signaling pathways such as MAPK (42), NF-κB (43), and GSK3β (44), ultimately contributing to HPD. In our report, it might be the alteration of the signal pathway caused by gene mutations that changed the TME, resulting in positive expression of PD-1, thereby causing a vicious cycle and leading to HPD.

In summary, the patient in our report harbors an inactivating TP53 P.F270V mutation, resulting in loss of tumor suppressor function and unchecked tumor cell proliferation. Additionally, this patient exhibits amplification of EGFR, MET, and FGFR-1, with MET copy number reaching 32.76, which may alter the TME through activation of multiple signaling pathways, enhancing tumor cell invasiveness and metastatic potential, likely serving as the primary cause of HPD in this case.

Although we observed HPD associated with Sintilimab, this retrospective case report cannot comprehensively reflect the heterogeneity of the disease or general patterns of therapeutic response. In addition, potential biases may exist in treatment selection and disease evaluation. Prospective studies with large cohorts are needed to validate these observations. Moreover, future studies should incorporate liquid biopsy techniques such as cfDNA, circulating tumor cells (CTCs), and exosomes. Genetic profiling of PD-1/PD-L1, EGFR, MET, and other relevant markers is also essential. In parallel, artificial intelligence (AI)-assisted decision-making should be applied to optimize comprehensive disease management.