Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy

Anna De Lucia ¹ Lucia Mazzotti ¹ Anna Gaimari ¹ Matteo Zurlo ¹ Roberta Maltoni ² Claudio Cerchione ³ Sara Bravaccini ⁴ Angelo Delmonte ⁵ Lucio Crinò ⁶ Patricia Borges de Souza ¹ Luigi Pasini ^1* Fabio Nicolini ¹ Fabrizio Bianchi ⁷ Manel Juan ⁸ Hugo Calderon ⁸ Chiara Magnoni ¹ Luca Gazzola ¹ Paola Ulivi ⁹ Massimiliano Mazza ¹

• ¹ Advanced Cellular Therapies and Rare Tumors Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori',, Meldola, Italy, Italy
• ² Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
• ³ Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
• ⁴ Faculty of Medicine and Surgery, "Kore" University of Enna, Enna, Italy
• ⁵ Medical Oncology Department, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
• ⁶ Medical Oncology Department, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy
• ⁷ Unit of Cancer Biomarker, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
• ⁸ Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
• ⁹ Translational Oncology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy

Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches. Since their introduction, over 20 years ago, targeted therapies with tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for NSCLC. Nowadays, targeted therapies remain the gold standard for many patients, but still they suffer from many adverse effects, including unexpected toxicity and intrinsic acquired resistance mutations, which lead to relapse. The adoption of immune checkpoint inhibitors (ICIs) in 2015, has offered exceptional survival benefits for patients without targetable alterations. Despite this notable progress, challenges remain, as not all patients respond favorably to ICIs, and resistance to therapy can develop over time. A crucial factor influencing clinical response to immunotherapy is the tumor microenvironment (TME). The TME is pivotal in orchestrating the interactions between neoplastic cells and the immune system, influencing tumor growth and treatment outcomes. Research on TME in lung cancer has revealed a complex and dynamic interplay between immune suppressive and immune activating cues. In this review, we discuss how the understanding of this intricate relationship is crucial for the success of immunotherapy and survey the current state of immunotherapy intervention, with a focus on forthcoming and promising chimeric antigen receptor (CAR) T cell therapies in NSCLC. The TME sets major obstacles for CAR-T therapies, creating conditions that suppress the immune response, inducing T cell exhaustion. To enhance treatment efficacy, specific efforts associated with CAR-T cell therapy in NSCLC, should definitely focus TME-related immunosuppression and antigen escape mechanisms, by combining CAR-T cells with immune checkpoint blockades.