Ferroptosis, necroptosis, and pyroptosis in the tumor microenvironment: Perspectives for immunotherapy of SCLC.

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by dismal prognosis. Although SCLC may initially respond well to platinum-based chemotherapy, it ultimately relapses and is almost universally resistant to this treatment. Immune checkpoint inhibitors (ICIs) have been approved as the first- and third-line therapeutic regimens for extensive-stage or relapsed SCLC, respectively. Despite this, only a minority of patients with SCLC respond to ICIs partly due to a lack of tumor-infiltrating lymphocytes (TILs). Transforming the immune "cold" tumors into "hot" tumors that are more likely to respond to ICIs is the main challenge for SCLC therapy. Ferroptosis, necroptosis, and pyroptosis represent the newly discovered immunogenic cell death (ICD) forms. Promoting ICD may alter the tumor microenvironment (TME) and the influx of TILs, and combination of their inducers and ICIs plays a synergistical role in enhancing antitumor effects. Nevertheless, the combination of the above two modalities has not been systematically discussed in SCLC therapy. In the present review, we summarize the roles of distinct ICD mechanisms on antitumor immunity and recent advances of ferroptosis-, necroptosis- and pyroptosis-inducing agents, and present perspectives on these cell death mechanisms in immunotherapy of SCLC.