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A study suggests that antibiotic use within one month of immune checkpoint inhibitor treatment may undermine survival in cutaneous squamous cell carcinoma. 

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced cutaneous squamous cell carcinoma (cSCC), but a recent study published in the European Journal of Cancer underscores the risk of concurrent antibiotic (ATB) exposure.

Investigators at Bordeaux University Hospital in France found that antibiotics prescribed within one month of ICI initiation were associated with significantly worse survival outcomes.

“The impact of antibiotics on immunotherapy efficacy has been suggested in other cancers but had not been specifically evaluated in cSCC, a population particularly vulnerable to antibiotic overuse due to frequent tumor ulceration and infection mimics,” wrote Anne Pham-Ledard, MD, PhD, and colleagues.

The single-center, retrospective study included 104 patients with locally advanced or metastatic cSCC treated with anti–PD–1 agents (cemiplimab, nivolumab, pembrolizumab) between March 2019 and July 2023. Patients were stratified into two key subgroups based on antibiotic exposure:

• ATB 3-3: Received antibiotics within 3 months before or after ICI start (45% of patients)
• ATB 1-1: Received antibiotics within 1 month before or after ICI start (20% of patients)

Most antibiotics were prescribed for suspected skin infections (60%), and the most common agents were beta-lactams (45%).

The median age of the patients was 78 years, and 75% were male. Most had nodal or metastatic disease, and baseline characteristics were similar between exposed and non-exposed groups.

Antibiotics Impair Survival & Disease Control

Patients in the ATB 1-1 group showed significantly worse outcomes:

• Progression-free survival (PFS): Median of 127 days vs 511 days in unexposed controls (P = .005)
• Overall survival (OS): Median 419 days vs not reached (P = .04)
• Disease-specific survival (SS): Median 419 days vs not reached (P = .01)

The 3-month disease control rate (DCR) was also lower in both exposed groups—38% in ATB 1-1 versus 66% in controls (P=0.018); and 49% in ATB 3-3 versus 70% in controls (P=0.027). Multivariate Cox regression confirmed the independent association of ATB 1-1 exposure with worse survival outcomes, adjusting for age, sex, and line of therapy. The hazard ratio for OS in the ATB 1-1 group was 0.46 (95% CI, 0.22–0.98; P=0.046).

“These findings support that antibiotic exposure within one month of ICI may be a critical period during which gut microbiota disruption can negatively influence immunotherapy outcomes,” authors noted.

Microbiota and Mechanisms

Prior studies in melanoma and lung cancer have shown that ATBs diminish the diversity of gut microbiota, impairing anti–PD–1 efficacy. Preclinical data have demonstrated that certain commensal bacteria, such as Bifidobacterium and Ruminococcaceae, enhance ICI response, and that fecal transplants from responders can restore responsiveness in animal models.

“This growing body of evidence, including our study, suggests that maintaining microbiota integrity is essential for optimal immunotherapy efficacy,” the authors wrote.

Clinical Implications & Caution

This study is among the first to examine the ATB–ICI interaction specifically in cSCC, a cancer marked by high tumor mutational burden and increasing ICI use. Given the tendency to overprescribe antibiotics in this population due to visible, ulcerated tumors, the findings highlight a potential modifiable risk factor.

Importantly, the survival divergence became most apparent after 400 days, suggesting the negative impact of antibiotics is not solely due to acute infection-related mortality.

“Antibiotic intake during the peri-immunotherapy period may independently affect outcomes,” the authors cautioned. “This is a warning for all practitioners, as antibiotics may be overused in advanced skin tumors.”

Though limited by its retrospective design, the study reinforces a call for prospective trials examining microbiota modulation strategies—such as antibiotic stewardship, bacterial profiling, or even microbiome restoration—to enhance ICI outcomes.

“Understanding which antibiotic classes, durations, or microbiota shifts have the most clinical relevance could reshape supportive care in immuno-oncology,” the authors concluded.