FAP‐Targeted Photodynamic Therapy Mediated by Ferritin Nanoparticles Elicits an Immune Response against Cancer Cells and Cancer Associated Fibroblasts

Abstract

Cancer‐associated fibroblasts (CAFs) are present in many types of tumors and play a pivotal role in tumor progression and immunosuppression. Fibroblast‐activation protein (FAP), which is overexpressed on CAFs, has been indicated as a universal tumor target. However, FAP expression is not restricted to tumors, and systemic treatment against FAP often causes severe side effects. To solve this problem, a photodynamic therapy (PDT) approach is developed based on ZnF16Pc‐loaded and FAP‐specific single chain variable fragment (scFv)‐conjugated apoferritin nanoparticles, or αFAP‐Z@FRT. αFAP‐Z@FRT PDT efficiently eradicates CAFs in tumors without inducing systemic toxicity. When tested in murine 4T1 models, the treatment elicits anti‐cancer immunity, causing suppression of both primary and distant tumors, that is, the abscopal effect. Treatment efficacy is enhanced when αFAP‐Z@FRT PDT is used in combination with anti‐PD1 antibodies. Interestingly, it is found that the PDT treatment not only elicits a cellular immunity against cancer cells, but also stimulates an anti‐CAFs immunity. This is supported by an adoptive cell transfer study, where T cells taken from 4T1‐tumor‐bearing animals treated with αFAP PDT retard the growth of A549 tumors established on nude mice. Overall, this approach is unique for permitting site‐specific eradication of CAFs and inducing a broad spectrum anti‐cancer immunity.

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

“… 338 , 380 , 381 In this regard, nanoparticles based on ZnF16pc loading and FAP-specific single-chain variable fragments or αFAP-Z@FRT can target FAP to effectively and safely deplete CAFs. 382 In addition to CAF depletion, sibrolizumab (an anti-FAP monoclonal antibody) has been shown to target and prevent the activation of FAP + CAFs to inhibit tumor growth. 383 , 384 From another perspective, Noggin (a BMP signaling pathway inhibitor) can reverse the pericyte-CAF transition to decrease the number of CAFs.…”

Bioengineered Ferritin Nanocarriers for Cancer Therapy

“…Li et al [68] developed a single chain variable fragment (scFv) sequence targeting FAP conjugated and ZnF16Pc contained ferritin nanoparticles (αFAP-Z@FRT), selectively killing CAFs under the action of PDT and increasing the relative uptake rate of tumors by more than 5 times (Figure 9). Zhou et al [69] found on the basis of the above research that PDT can induce cellular immunity to cancer cells and also stimulate immunity against CAFs. In bilateral 4T1 tumor models, after αFAP-Z@FRT were injected into animals, the primary tumors were irradiated with laser, and the contralateral tumors were unirradiated.…”

Two‐Photon Absorption Induced Cancer Immunotherapy Using Covalent Organic Frameworks

“…PDT has been denoted as an ICD inducer and triggers the immune infiltration in multitype of tumors. [17] To explore the immunogenic effect of COF606 mediated 2PA PDT on inducing cell death, three representative DAMPs ATP, CRT, and HMGB1, were detected. [17c,18] ATP, which functions as a crucial "find me" signal that recruits phagocytes and initiates antitumor immunity, [19] was continuously released from 4T1 cells after treatment with COF606 + laser, while the control group showed very little detectable ATP release (Figure 3A; Figure S12, Supporting Information).…”