**Background:** The concept of cancer immunoediting, introduced by Schreiber in 2002, describes the dual role of the immune system in both inhibiting and promoting tumor formation through three phases: elimination, equilibrium, and escape. In the elimination phase, innate and adaptive immunity synergize to destroy malignant cells before clinical detection. Surviving tumor cells enter the equilibrium phase, where proliferation is arrested but cells persist, often for years or decades. Eventually, tumor cells enter the escape phase, where they express immunosuppressive ligands, downregulate MHC class I molecules, and create a complex immunosuppressive tumor microenvironment (TME). Most clinically diagnosed tumors are already in the escape phase, where existing single-target therapies often fail due to high heterogeneity and immunotherapy resistance. The authors propose a new therapeutic concept—'counter-immunoediting therapy'—which aims to identify the current immunoediting phase and apply precise interventions to retrograde the process, returning escape-phase tumors to equilibrium or elimination phases.
**Methods:** This is a narrative review summarizing the characteristics of each cancer immunoediting phase and corresponding therapeutic tools. The authors propose a reclassification of the TME into four immunophenotypes based on driving factors: (1) oncogene-driven type (cold tumors, low TMB, poor ICI response), (2) stromal cell-driven type (cold tumors, abnormal vasculature, poor effector infiltration), (3) immunosuppressive cell-driven type (hot tumors, high Treg/MDSC/TAM infiltration, better ICI response), and (4) exhausted T cell-driven type (hot tumors, terminally exhausted T cells resistant to ICI). For each phenotype, three normalization strategies are described: normalization of stromal cells (targeting VECs, CAFs, pericytes, MSCs), normalization of immunity (targeting inhibitory immune receptors, immunosuppressive cells, exhausted immune cells, and adoptive cellular therapy), and normalization of tumor cells (inducing antigen expression, targeting inhibitory ligands, decreasing tumor cell viability). The review also discusses interventions for the equilibrium phase (neoadjuvant immunotherapy, cancer vaccines including mRNA vaccines) and elimination phase (exercise, nutrition, mental health, sleep).
**Key Results:** The review compiles data from multiple clinical trials. For CAR-T therapy in diffuse large B-cell tumors, three trials reported complete remission (CR) in 40% of 93 patients, 58% of 101 patients, and 53% of 256 patients. In multiple myeloma, an early trial showed CR in 45% of 33 patients, and a meta-analysis reported 44.8% CR among 640 patients. For adoptive TIL therapy, 9 of 15 metastatic melanoma patients achieved objective remission; in cervical cancer, 9 of 12 patients achieved CR (NCT04443296); in lung adenocarcinoma, 11 of 16 patients had initial tumor regression. The IMpower150 trial demonstrated improved median overall survival with atezolizumab-bevacizumab-carboplatin-paclitaxel versus bevacizumab-carboplatin-paclitaxel (19.5 months vs. 14.7 months). A phase II trial of sintilimab plus anlotinib in PD-L1-positive advanced cervical cancer (42 patients) showed an ORR of 54.8% and disease control rate of 94.9%. Neoadjuvant nivolumab for resectable early-stage lung cancer (21 patients) produced a major pathologic response in 45% of 20 patients. For mRNA vaccines, a personalized neoantigen vaccine for melanoma induced immune responses in all patients and reduced cumulative recurrence; in another trial (NCT01970358), 4 of 6 patients achieved long-term PFS. The review also notes that 29% to 34% of persistent ground-glass lung nodules are malignant, and that spontaneous regression of melanoma occurs in 20% to 30% of cases.
**Clinical Implications:** Counter-immunoediting therapy represents a paradigm shift from traditional single-target, single-drug treatment to a systematic, phase-based precision immunotherapy approach. By identifying the specific immunoediting phase and TME immunophenotype, clinicians can select appropriate normalization strategies—stromal, immune, or tumor cell—either alone or in combination/sequence. This approach may overcome resistance to immune checkpoint inhibitors, particularly in cold tumors and tumors with terminally exhausted T cells. The combination of anti-angiogenic therapy with ICI therapy is clinically validated (e.g., IMpower150). For equilibrium-phase tumors, neoadjuvant immunotherapy and cancer vaccines (including mRNA vaccines) may prevent progression to escape phase. For elimination phase, lifestyle interventions (exercise, nutrition, mental health, sleep) that enhance innate immunity are emphasized. The authors conclude that with advances in AI and multidimensional TME assessment, counter-immunoediting therapy could become the most promising strategy for curing cancer.