T cell-based immunotherapies are facing great challenges in the recruitment and activation of tumor-specific T cells against solid tumors. Among which, utilizing nanobody (Nb) or nanobodies (Nbs) to construct T cell engager has emerged as a more practical potential for enhancing the anti-tumor effectiveness of T cells. Here, we designed a new Nb-guided multifunctional T cell engager (Nb-MuTE) that not only recruited effector T cells into the tumor tissues, but also efficiently activated T cells anti-tumor immunity when synergies with photothermal effect. The Nb-MuTE, which was constructed based on an indocyanine green (ICG)-containing liposome with surface conjugation of CD105 and CD3 Nbs, and showed excellent targetability to both tumor and T cells, following enhancement of activation, proliferation and cytokine secretion of tumor-specific T cells. Notably, the immunological anti-tumor functions of Nb-MuTE-mediated T cells were further enhanced by the ICG-induced photothermal effect in vitro and in vivo. Such a new platform Nb-MuTE provides a practical and “all-in-one” strategy to potentiate T cell responses for the treatment of solid tumor in clinic.

Developing a novel therapeutic approach to prevent and treat hepatocellular carcinoma (HCC) is essential. As an adoptive cell therapy candidate, cytokine-induced killer (CIK) cell immunotherapy is ideal. However, for efficacy in vivo delivery of CIK cells conjugate with antibody antineoplastic agents into the cancer cells, various biological obstacles including rapid degradation in vivo and the absence of active targeting capability need to be overcome. Previously, we developed a fusion antibody-chemokine protein which contained human Endoglin antibodies and human Interferon-gamma-induced protein 10 (hENG scFv/hIP-10). To this end, we present that a novel synthesized TLS11a-Lipo-hENG scFv/hIP-10 nanocapsules, which combine the advantages of prolonged half-life and good stability liposomes and HCC-specific targeting aptamer “TLS11a,” would be able to realize efficient and effective in vivo therapy. Also, we find that in combination with CIK cells possess a greater anti-hepatocarcinoma efficacy. Combined with TLS11a-Lipo-hENG scFv/hIP-10 nanocapsules and CIK cells, they could suppress tumor growth and prolong the survival of hepatoma-bearing mice through recruiting endogenous CIK cells in tumor tissues, inhibiting cell proliferation in tumors while promoting apoptosis and producing IFN-γ level. It appears that TLS11a-Lipo-hENG scFv/hIP-10 nanocapsules can enhance the antitumor activity of CIK cells against human hepatocellular carcinoma.

Photothermal therapy (PTT) is a local treatment that uses photothermal conversion agents (PTAs) to absorb light and produce heat in tumor tissue. The direct result is tumor ablation. At the same time, heat-damaged tumor cells may undergo immunogenic cell death (ICD). This process is often accompanied by the release of damage-associated molecular patterns (DAMPs), followed by dendritic cell activation and antigen presentation. Because of this immune effect, PTT has been explored as a partner for immunotherapy. It may be useful in tumors where antigen presentation is weak or where the immune microenvironment is highly suppressive. However, local heating alone usually cannot produce a long-lasting systemic immune response. Its effect on distant metastasis is also limited. For this reason, PTT is now often combined with immune checkpoint blockade, adoptive cell therapy, cancer vaccines, and other immune-based strategies. This review discusses the link between PTT-induced tumor damage and antitumor immune activation. It classifies and compares the structural optimization ideas, optical properties, biological safety, and application limitations of organic and inorganic photothermal materials. It summarizes the six mainstream combination schemes of photothermal therapy with immune checkpoint inhibitors, adoptive cell therapy, tumor vaccines, cytokine therapy, oncolytic virus therapy, and bispecific antibody therapy. It analyzes the synergistic anti-tumor mechanisms and the latest preclinical research progress of various combination strategies. Finally, it sorts out the core bottlenecks that restrict the clinical transformation of photothermal immunotherapy and proposes corresponding optimization development prospects.