The clinical breakthrough of immune checkpoint blockades (ICB) has yielded a new era of cancer immunotherapy. Several immune checkpoints of adaptive immune system have been identified during decades, such as programmed cell death protein 1 (PD1), programmed death-ligand 1 (PDL1) and cytotoxic T-lymphocyte antigen 4 [1]. To date, seven ICB have been approved by the United States Food and Drug Administration, six of which are antibodies against PD1/PDL1 axis [2]. Clinical efficacy of these antibodies has been confirmed superior to the conventional therapeutic approaches [3]. Whereas, there are some drawbacks of anti-PD1/PDL1 therapies, especially the limited response rates and relatively high recurrence rates caused by primary and acquired resistance [4].

Precise understanding of mechanism underlying tumor progression reveals that innate immune system cooperates with adaptive immune system in shaping tumor growth, and plays specialized roles in eliminating tumor cells [1]. Cluster of differentiation 47 (CD47), ‘marker of self’, is normally expressed on the surface of all cells and binds to signal regulatory protein alpha (SIRPα) on macrophages and other myeloid cells, yielding an inhibitory signal to innate immune system [5]. CD47 is overexpressed in different types of cancers and has been confirmed as a predictor of poor prognosis [6], [7], [8], [9]. Monotherapy by anti-CD47 antibody preferentially enables phagocytosis of tumor cells by macrophages, and cross primes T cell responses, leading to the destruction of tumor [10], [11], [12]. In rational-designed combination treatment, anti-CD47 antibody works as an adjuvant therapy, which synergizes with anti-PD1/PDL1 antibodies. By priming both adaptive immune and innate immune, combination treatment induces phagocytosis and T cell cytotoxicity, resulting in better anti-tumor immunity [13], [14], [15], [16].

Despite enormous effort made in the development of antibody based ICB and rational-designed combination treatment, the response to ICB is heterogeneous across tumor types [17]. Microsatellite stable (MSS) colorectal cancer, associated with lower tumor mutation burden and less immune infiltration, has long been considered resistant to immunotherapy [18]. Researches highlight the importance of immunosuppressed tumor microenvironment (TME) in the resistance to ICB. By diminishing the immune response, TME contributes to the primary and acquire resistance, and remains a major impediment in the efficacy of ICB immunotherapy [17], [19], [20]. Emerging studies reveal that therapeutic vaccine, offering the opportunity to reprogram TME and provoke systemic immune responses, seems an appealing solution to the resistance to ICB immunotherapy [21], [22], [23]. Nevertheless, conventional vaccine based on autologous protein has little effect on reprograming TME, since immune system is tolerant to autologous protein. Thus, breaking self-tolerance to autologous protein has been a crucial issue to the efficacy of therapeutic vaccine.

In our previous work, we developed a Nitrated T cell epitope named NitraTh by substituting p-nitro-L-phenylalanine for alanine at position 11 of universal T cell epitopes (Pan DR epitope, PADRE). NitraTh could help autologous proteins break immune tolerance in both mouse and human immune systems [24]. Vaccination of PDL1–NitraTh, a PDL1-targeted vaccine based on NitraTh, can inhibit tumor growth by inducing the PDL1-specific immune response and increasing tumor lymphocyte infiltration [25]. In this study, a CD47-targeted vaccine, namely CD47-NitraTh, was constructed and confirmed to repress the progression of tumor by inducing tumor-specific immune response. Furthermore, combination treatment of both CD47-NitraTh and PDL1–NitraTh could enhance macrophage-mediated phagocytosis for tumor cells, and promote the activation and infiltration of T cells. Notably, by activating chemokine signaling pathway, NitraTh based vaccines reversed immunosuppressed TME, resulting in improved therapeutic outcome for tumor. With the advantage of reversing immunosuppressed TME, NitraTh based vaccine seems a promising approach for anti-tumor immunotherapy.