Preventing post-transplant squamous cell carcinoma: Q-2361 reverses tacrolimus-induced keratinocyte transformation

Solid organ transplant recipients face a 65–250-fold increased risk of cutaneous squamous cell carcinoma (cSCC) due to lifelong calcineurin inhibitor immunosuppression. Tacrolimus, the predominant immunosuppressant used in over 95% of transplant regimens worldwide, contributes to this elevated cancer risk through two mechanisms: suppression of anti-tumor T cell immunity and direct carcinogenic transformation of keratinocytes, independent of immune function.
This study evaluated whether Q-2361, a first-in-class tacrolimus antagonist, can reverse tacrolimus-induced keratinocyte transformation, offering a novel, localized prevention strategy that preserves systemic transplant tolerance. Using human HaCaT cells and in vivo mouse models, we assessed the effects of tacrolimus and Q-2361 on UV-induced keratinocyte responses. Key endpoints included NF-κB nuclear translocation, activation of DNA repair pathways (XPC, DDB1, and global nucleotide excision repair), production of pro-inflammatory cytokines (IL-6 and TNF-α), apoptosis, and pAKT signaling. Long-term studies tested topical Q-2361 in nude mice receiving systemic tacrolimus for 31 weeks under thrice-weekly UVB irradiation to evaluate tumor prevention in vivo.
Tacrolimus inhibited keratinocyte stress responses to UVB, blocking NF-κB activation, cytokine production, apoptosis, and nucleotide excision repair, while promoting proliferation. Low-dose Q-2361 (10–20-fold above tacrolimus levels) fully restored these protective responses, normalizing NF-κB activity, cytokine signaling, apoptosis, and DNA repair protein expression. In vivo, topical Q-2361 reactivated IL-6 and DNA repair genes, reduced pAKT expression, and notably prevented tumor formation in tacrolimus-treated, UV-irradiated mice, demonstrating robust cancer prevention at the tissue level.
These findings define a new paradigm in post-transplant cancer prevention: localized tacrolimus antagonism can avert cSCC by restoring keratinocyte-autonomous defense mechanisms independent of systemic immune modulation. Q-2361 thus represents a potentially transformative topical therapy that resolves the long-standing clinical dilemma between maintaining life-saving immunosuppression and mitigating fatal skin cancer risk, paving the way for clinical translation in over 500,000 transplant recipients worldwide who remain at high risk.