The cathelicidin antimicrobial peptide (CAMP) is overexpressed in cutaneous squamous cell carcinoma and promotes tumor growth through a vicious cycle involving S1P signaling, FPRL1 receptor activation, and suppression of anti-tumor immunity.
Vicious cycle identifiedER stress → S1P → CAMP → tumor growth → ER stress creates a self-reinforcing cancer-promoting loop in skin squamous cell carcinoma
What the researchers found
CAMP is overexpressed in cSCC and promotes tumor growth via FPRL1 receptor. S1P signaling drives CAMP production; inhibiting S1P reduces CAMP-stimulated cSCC growth. CAMP increases FOXP3+ regulatory T cells (suppressing anti-tumor immunity) and induces ER stress, creating a vicious S1P-CAMP feedback loop that favors cSCC development.
Why it matters
Understanding that a normally protective antimicrobial peptide can be hijacked by cancer cells reveals a new therapeutic target. Blocking the S1P-CAMP-FPRL1 axis could provide a novel approach to treating skin cancer while preserving the peptide's antimicrobial benefits in healthy tissue.
The numbers in context
CAMP expression increased in cSCC cells and patient skin. S1P levels elevated in cSCC cells. Blocking S1P production or FPRL1 receptor attenuated cSCC growth. FOXP3+ regulatory T cells increased in cSCC skin.
How the study worked
Combination of patient tissue analysis, in vitro cSCC cell line experiments, receptor blockade studies (FPRL1), S1P pathway inhibition, invasion assays using fibroblast/ECM substrates, and regulatory T cell quantification.
Who was studied
Cutaneous squamous cell carcinoma cells and patient skin samples
What this study cannot tell us
Primarily in vitro and ex vivo evidence. No in vivo tumor treatment studies. The relative contribution of CAMP to cSCC development versus other UV-driven pathways is not quantified. Clinical implications of CAMP as a therapeutic target need validation.
How to read the evidence
Mechanistic study combining patient tissue analysis with detailed in vitro pathway dissection. Strong mechanistic evidence but lacks in vivo therapeutic validation.
When this study was published
Published in 2025; adds to understanding of cathelicidin's complex roles beyond antimicrobial defense.
The bigger picture
This study highlights the dual nature of antimicrobial peptides—protective against infection but potentially cancer-promoting when dysregulated. As cathelicidin-based therapies are explored for infections and wound healing, understanding this cancer risk is critical for safe clinical development.
Questions still open
- Could FPRL1 receptor antagonists be developed as topical treatments for cSCC or precancerous skin lesions?
- Does chronic UV exposure-induced CAMP elevation contribute to cSCC risk in high-exposure populations?
- Are patients with elevated skin cathelicidin (e.g., rosacea patients) at increased risk for cSCC?
Common questions
Can an antimicrobial peptide cause cancer?
Could blocking cathelicidin help treat skin cancer?
Read the original research
Sphingosine-1-Phosphate-Cathelicidin Axis Plays a Pivotal Role in the Development of Cutaneous Squamous Cell Carcinoma.
The Journal of investigative dermatology, 145(4), 854-863.e6
Citation
Park, Kyungho; Shin, Kyong-Oh; Kim, Young-Il; Nielsen-Scott, Anna L; Mainzer, Carine; Celli, Anna; Bae, Yoojin; Chae, Seungwoo; An, Hahyun; Choi, Yerim; Park, Jae-Ho; Park, Soo-Hyun; Hwang, Jin-Taek; Kang, Seung Goo; Wakefield, Joan S; Arron, Sarah T; Holleran, Walter M; Mauro, Theodora M; Elias, Peter M; Uchida, Yoshikazu. (2025). Sphingosine-1-Phosphate-Cathelicidin Axis Plays a Pivotal Role in the Development of Cutaneous Squamous Cell Carcinoma.. The Journal of investigative dermatology, 145(4), 854-863.e6. https://doi.org/10.1016/j.jid.2024.08.008