Introduction: Neoadjuvant immune checkpoint inhibitors have transformed the management of mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer, achieving unprecedented pathological response rates. Experimental evidence suggests that cyclooxygenase-2 (COX-2) inhibition may enhance antitumor immunity by modifying the inflammatory tumor microenvironment, providing a rationale for combining celecoxib with PD-1 blockade.
Introduction:
Neoadjuvant immune checkpoint inhibitors have transformed the management of mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer, achieving unprecedented pathological response rates. Experimental evidence suggests that cyclooxygenase-2 (COX-2) inhibition may enhance antitumor immunity by modifying the inflammatory tumor microenvironment, providing a rationale for combining celecoxib with PD-1 blockade.
Problem Statement:
Although neoadjuvant PD-1 inhibitor monotherapy produces excellent outcomes in dMMR/MSI-H colorectal cancer, a substantial proportion of patients still have residual viable tumor after treatment. Whether adding celecoxib can further improve pathological complete response without compromising safety has remained uncertain.
Summary:
The multicenter phase 2 PICC-2 trial evaluated neoadjuvant toripalimab plus celecoxib versus toripalimab alone in patients with locally advanced dMMR/MSI-H colorectal cancer. The combination significantly increased the proportion of patients achieving pathological complete response compared with PD-1 inhibitor monotherapy, while maintaining a comparable safety profile. Nearly all patients successfully completed neoadjuvant treatment and proceeded to surgery, demonstrating the feasibility of this strategy in routine clinical practice. Importantly, the addition of celecoxib did not increase severe treatment-related toxicity, and no new safety concerns emerged. These findings support the concept that targeting COX-2–mediated inflammation can enhance the effectiveness of immune checkpoint blockade in this highly immunogenic tumor subtype. If confirmed in larger phase 3 studies, combining celecoxib with neoadjuvant PD-1 inhibition may become an inexpensive, readily accessible approach to maximize pathological response and further improve organ preservation and long-term oncologic outcomes in patients with dMMR/MSI-H locally advanced colorectal cancer.
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