Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients.

Despite the great advancements in treatment strategies for hematological malignancies (HMs) over the years, their effective treatment remains challenging. Conventional treatment strategies are burdened with several serious drawbacks limiting their effectiveness and safety. Improved understanding of tumor immunobiology has provided novel anti-cancer strategies targeting selected immune response components. Currently, immunotherapy is counted as the fourth pillar of oncological treatment (together with surgery, chemo- and radiotherapy) and is becoming standard in the treatment regimen, alone or in combination therapy. Several categories of immunotherapies have been developed and are currently being assessed in clinical trials for the treatment of blood cancers, including immune checkpoint inhibitors, antigen-targeted antibodies, antibody–drug conjugates, tumor vaccines, and adoptive cell therapies. However, monoclonal antibodies (mAbs) and their derivatives have achieved the most notable clinical outcome so far. Since the approval of rituximab for treating B-cell malignancies, the availability of mAbs against tumor-specific surface molecules for clinical use has flourished. Antibody-based therapy has become one of the most successful strategies for immunotherapeutic cancer treatment in the last few decades, and many mAbs have already been introduced into standard treatment protocols for some hematologic malignancies. To further increase the efficacy of mAbs, they can be conjugated to radioisotopes or cytostatic drugs, so-called antibody–drug conjugates. Moreover, with the growing recognition of T-cell immunity’s role in cancer development, strategies aimed at enhancing T cell activation and inhibiting mechanisms that suppress T cell function are actively being developed. This review provides a comprehensive overview of the current status of immunotherapeutic strategies based on monoclonal antibodies and their derivatives, including antibody–drug conjugates, bispecific T-cell engagers, and checkpoint inhibitors, approved for the treatment of various HMs.