Single in situ intratumoral low-dose shikonin hydrogel plus mild photothermal therapy elicits systemic antitumor immunity in immune-cold triple-negative breast cancer

Abstract

Shikonin (SHK) possesses potent antitumor activity; however, its severe non-selective toxicity greatly limits the feasibility of conventional systemic administration for cancer therapy. Likewise, mild photothermal therapy (PTT) has intrinsic limitations, including inadequate induction of immunogenic cell death (ICD) and compensatory activation of immunosuppressive pathways, such as increased IDO1 activity and PD-L1 expression. In the present study, low-dose SHK and gold nanorods were co-encapsulated within a supramolecular hydrogel (mPECT) and administered by intratumoral injection to achieve localized combination therapy with mild PTT. Mild PTT rapidly triggered antitumor immune activation within the immunosuppressive tumor microenvironment, whereas SHK sustained this response by suppressing PTT-induced IDO1 activation and PD-L1 upregulation and by markedly enhancing ICD. The mPECT hydrogel enabled prolonged local retention and controlled release of SHK, minimizing rapid systemic exposure while preserving therapeutic efficacy at the tumor site. This localized combination of SHK and mild PTT elicited a robust adaptive antitumor immune response that not only inhibited primary tumor growth but also suppressed the progression of untreated distant tumors and generated durable antitumor immune memory. These findings indicate that a single intratumoral administration of low-dose SHK-loaded hydrogel combined with mild PTT can induce potent systemic antitumor immunity, supporting the further development of localized SHK-based therapeutic strategies for the treatment of immune-cold tumors.