Esophageal carcinoma constitutes a major global health burden, ranking as the seventh most common malignancy and the sixth leading cause of cancer-associated mortality worldwide. Significant geographical disparities exist, with Eastern Asian populations experiencing a disproportionately high incidence (Sung et al., 2021). Histologically, esophageal carcinoma is subclassified into two main subtypes: squamous cell carcinoma (ESCC) and adenocarcinoma. Notably, ESCC constitutes the predominant pathological variant, representing approximately 87 % of all diagnosed cases according to global epidemiological registries (Yeung and Elimova, 2022). Traditional chemotherapy regimens (e.g., cisplatin plus paclitaxel) are associated with limited efficacy, with median OS typically under 1 year and substantial toxicity (Doki et al., 2022). Reported outcomes for such regimens include median OS of 9.8–12 months, median PFS of 5.5 months, and ORR of 30–40 %. By contrast, combinations with immunotherapy appear to extend median OS by approximately 3–4 months and improve ORR by 20–30 % (Sun et al., 2021). Consequently, chemotherapy now primarily functions as a backbone for immunotherapy combinations. For example, PD-1 inhibitors (e.g., camrelizumab, nivolumab, toripalimab) combined with chemotherapy have become the first-line standard of care for advanced ESCC. In the ESCORT-1st trial, camrelizumab plus chemotherapy significantly improved OS and PFS: median OS reached 12.6 months (vs. 9.8 months in controls; HR=0.72, 28 % mortality risk reduction), while median PFS was 6.9 months (vs. 5.5 months in controls; HR=0.56, 44 % progression risk reduction) (He et al., 2024). Despite these improvements, the prognosis for advanced ESCC remains poor, necessitating novel therapeutic strategies.

For more than half a century, cytotoxic chemotherapy has been a fundamental pillar of oncologic treatment, especially in settings with limited alternatives. Pharmacological optimization of chemotherapeutics represents a key strategy for enhancing efficacy. Conventional paclitaxel formulations, which utilize polyethoxylated castor oil and ethanol as solubilizing agents, are linked to clinically significant toxicities—notably severe hypersensitivity reactions and dose-limiting neurotoxicity. These often require prophylactic antihistamines and frequent dose reductions, ultimately compromising drug exposure and pharmacokinetics. Current treatment paradigms for locally advanced ESCC highlight the synergy between paclitaxel-based chemotherapy and radiation therapy. Mitigating treatment-related toxicities while improving treatment adherence could significantly improve survival outcomes by optimizing the therapeutic index.

The development of nanomedicine has advanced oncologic drug delivery, with nanoparticle technologies enabling more precise tumor targeting through enhanced permeability and retention (EPR) effects (Luo et al., 2022, Tan et al., 2021). This approach maximizes cytotoxic payload delivery while minimizing systemic exposure. Studies have validated the toxicity-reducing properties of nanocarrier-based drug delivery systems in chemotherapy (Wei et al., 2021, Norouzi and Hardy, 2021). Among these, polymeric micellar nanoparticles represent a leading paclitaxel formulation, with phase III trial data supporting their clinical utility (Lu et al., 2022). Particularly notable is the dose-escalated regimen of polymeric micellar paclitaxel (Pm-Pac, 230 mg/m²). In first-line NSCLC treatment, Pm-Pac demonstrated significantly improved ORR (+34.5 %, p < 0.01) and PFS (HR=0.62, 95 %CI: 0.51–0.75) compared to conventional paclitaxel(175 mg/m²), with comparable safety (Shi et al., 2021).

Emerging evidence suggests that combining immune checkpoint inhibitors (ICIs) with chemotherapeutic agents can enhance antitumor effects through multimodal mechanisms (Yi et al., 2022, Harrington et al., 2023). At the molecular level, the PD-1/PD-L1 axis is a key regulator of tumor immune surveillance. Tumor cells exploit this pathway by overexpressing PD-L1 to induce T-cell exhaustion, thereby promoting immune escape and suppressing immunogenic cell death (Zheng et al., 2023, Wu et al., 2019, Zhou et al., 2023). Cytotoxic chemotherapeutics are recognized to have dual mechanisms: direct tumor killing and immunomodulation—such as depleting immunosuppressive Tregs (regulatory T cells) and enhancing neoantigen presentation (Yi et al., 2022, Harrington et al., 2023). This synergy has reshaped the therapeutic landscape for advanced ESCC, where first-line regimens increasingly integrate PD-1 inhibitors with platinum-based chemotherapy. Tislelizumab, a humanized IgG4 monoclonal antibody targeting PD-1, has engineered Fc domain modifications that minimize Fcγ receptor binding on macrophages. This design reduces antibody-dependent phagocytosis, potentially preserving effector T cells and extending therapeutic durability (Zhang et al., 2018). Some phase III trial data support the efficacy and manageable safety of tislelizumab-chemotherapy combinations in ESCC (Shen et al., 2020, Abushanab et al., 2023).

While nanocarrier-based Pm-Pac has demonstrated improved therapeutic indices in prior studies, its application in ESCC remains investigational. To address this gap, this phase II trial aims to evaluate the novel triple regimen (Pm-Pac/cisplatin/tislelizumab) in treatment-naïve advanced ESCC patients, systematically assessing its efficacy and safety.