Antimicrobial peptide cathelicidin promotes skin cancer growth through a sphingosine-1-phosphate feedback loop
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Vicious cycle identified ER stress → S1P → CAMP → tumor growth → ER stress creates a self-reinforcing cancer-promoting loop in skin squamous cell carcinoma
- Evidence Grade:
- Mechanistic study combining patient tissue analysis with detailed in vitro pathway dissection. Strong mechanistic evidence but lacks in vivo therapeutic validation.
- Study Age:
- Published in 2025; adds to understanding of cathelicidin's complex roles beyond antimicrobial defense.
- Original Title:
- Sphingosine-1-Phosphate-Cathelicidin Axis Plays a Pivotal Role in the Development of Cutaneous Squamous Cell Carcinoma.
- Published In:
- The Journal of investigative dermatology, 145(4), 854-863.e6 (2025)
- Authors:
- 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
- Database ID:
- RPEP-12961
Evidence Hierarchy
Frequently Asked Questions
Can an antimicrobial peptide cause cancer?
Not directly, but this study shows cathelicidin (CAMP) can promote existing skin cancer growth. UV damage triggers both CAMP production and cancer mutations. While CAMP normally protects against infection, in already-cancerous tissue it stimulates tumor growth, invasion, and immune evasion through a feedback loop with S1P signaling.
Could blocking cathelicidin help treat skin cancer?
The study suggests targeting the CAMP receptor (FPRL1) or the S1P signaling pathway that drives CAMP production could slow skin cancer growth. This would be a selective approach that disrupts the cancer-promoting cycle without eliminating CAMP's antimicrobial benefits in healthy skin.
Read More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-12961APA
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
MLA
Park, Kyungho, et al. "Sphingosine-1-Phosphate-Cathelicidin Axis Plays a Pivotal Role in the Development of Cutaneous Squamous Cell Carcinoma.." The Journal of investigative dermatology, 2025. https://doi.org/10.1016/j.jid.2024.08.008
RethinkPeptides
RethinkPeptides Research Database. "Sphingosine-1-Phosphate-Cathelicidin Axis Plays a Pivotal Ro..." RPEP-12961. Retrieved from https://rethinkpeptides.com/research/park-2025-sphingosine1phosphatecathelicidin-axis-plays-a
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.